Biology subjects

Kaul, M.

Publications and source records attributed to Kaul, M..

7 recordsLinked to original sources

bioRxiv2026

CD73-derived adenosine at the blood-brain barrier confers protection in a mouse model of ischemic stroke

Ischemic stroke remains a leading cause of death and disability, and current reperfusion therapies do not address the secondary neuroinflammatory response following blood-brain barrier (BBB) disruption. Purinergic signaling critically regulates this process: extracellular ATP promotes inflammation, whereas its enzymatic conversion into adenosine exerts tissue-protective effects. Notably, the ectonucleotidase CD73 (NT5E), which catalyzes AMP-to-adenosine conversion, is highly expressed by human but not murine brain endothelial cells (BECs). Here, we investigated the role of endothelial CD73 in ischemic stroke using an AAV vector engineered for selective transduction of murine BECs to induce BBB-specific CD73 expression. Endothelial CD73 enhanced extracellular ATP degradation toward adenosine generation and established a purine metabolism profile resembling that of human BECs. In the transient middle cerebral artery occlusion (tMCAO) mouse model, BBB-targeted CD73 expression reduced infarct volume by 40% and prevented early mortality within 48 h after reperfusion. Transcriptomic and flow cytometric analyses revealed altered leukocyte responses, including increased recruitment of monocytes/macrophages whose gene expression signatures were consistent with inflammation-resolving programs. These findings identify endothelial CD73 as an important regulator of post-ischemic neuroinflammation and highlight species-specific differences in BBB purine metabolism with implications for translational stroke research.

neuroscience↗

bioRxiv2026

Machine Learning Ensemble Reveals Distinct Molecular Pathways of Retinal Damage in Spaceflown Mice

BackgroundSpaceflight-associated neuro-ocular syndrome (SANS) poses significant risks to astronaut visual health during long-duration missions, yet its underlying molecular mechanisms remain incompletely understood. Oxidative stress and apoptosis are candidate molecular drivers, but their transcriptomic signatures in spaceflight-exposed retinal tissue have not been systematically characterized. MethodsWe applied a machine learning ensemble of linear regression models to predict two ocular phenotypes: 4-hydroxynonenal (4-HNE) immunostaining as a marker of lipid peroxidation-mediated oxidative damage; and TUNEL positivity as a marker of apoptotic cell death. In this observational study, we use bulk retinal gene expression data obtained from a controlled experiment with ground control and spaceflown mice to predict these phenotypes. Gene Ontology pathway enrichment was performed on the most predictive gene sets for each phenotype. ResultsThe 4-HNE phenotype was predicted by genes that converge on membrane-associated pathways, photoreceptor protein modification, synaptic dysfunction, and extracellular matrix dysregulation, including B2m, Tf, Cnga1, mt-Nd1, Snap25, and Efemp1. The genes predicting the TUNEL phenotype revealed a distinct signature emphasizing stress-induced apoptosis, rod photoreceptor degeneration, and endoplasmic reticulum dysfunction, with Ddit4, Nrl, Rom1, Reep6, and Gabarapl1 emerging as central regulators. ConclusionsOxidative lipid peroxidation and apoptotic cell death represent complementary and molecularly distinct pathological mechanisms in spaceflight-exposed murine retinal tissue. The gene signatures provide a putative molecular framework for developing noninvasive biomarkers and therapeutic targets to monitor and protect astronaut visual health during long-duration and deep-space missions.

bioinformatics↗

bioRxiv2025

Human Stress Response Specificity through Bioresonance Selectivity

Bold First ParagraphIn eukaryotes, the mitogen activated protein kinase (MAPK) cascade, a multilayered interconnected network of enzymes, connects external stimuli to gene regulation, determining cellular fate 1. Environmental stress sensed by a cell starts a complex chain of reactions between MAPK enzymes that ultimately activates the master stress response regulator protein p38 MAPK 2,3. Thus activated, p38 must then selectively activate targets from a pool of hundreds to initiate appropriate cellular responses 3. Mechanisms for how p38 performs this selection remain unclear 4,5. Here we show that human p38 target selectivity is based on the same principles as modern electronic telecommunications systems, except using waves of chemicals rather than electromagnetic fields or electric currents. p38 encodes information about stimuli as different frequency oscillations of its activation state, and targets are selected through frequency-dependent resonance of oscillating biochemical reactions between p38 and its targets. We demonstrate this mechanism by activating various genetic responses in human cells by applying only sugar at different frequencies. These results unify observations of oscillating signaling components and altered responses 6-19 into a coherent framework to understand and control human gene expression. As failures of this mechanism may contribute to some p38-associated diseases 2,20-28, these findings may have implications for pharmaceutical development and therapeutic strategies.

biophysics↗

bioRxiv2024

Magnesium hydroxide nanoneedles derived from Anthocleista schweinfurthii Gilg (Loganiaceae) support mesenchymal stromal cell proliferation and wound healing

Multiple metallic nanoparticles are able to promote cellular and tissue health, but these nanoparticles can be difficult to synthesize and can also cause unintended side-effects. Here, we study the effects on wounds healing and bone reparation of Mg(OH)2 from Anthocleista schweinfurthii Gilg (Loganiaceae) leaves (AS), which are local to the Africa region and have been used in traditional medicine to treat injuries. Mg(OH)2 nanoneedles were synthesized from aqueous extracts of Anthocleista schweinfurthii Gilg (Loganiaceae) leaves (AS) and magnesium nitrate. The quick polydispersing and crystallized Mg(OH)2-metal interface was found to be covered in plant secondary metabolites. We call this compound Mg(OH)2-AS. Using an acute dermal toxicity experiment on animal model, we determined that Mg(OH)2-AS is safe for topical application. In vitro experiments suggest that Mg(OH)2-AS has anti-inflammatory potential, and in vivo wound healing assays in Wistar rats indicate that Mg(OH)2-AS can enhance wound healing. To investigate Mg(OH)2-AS effects on the cellular level, we used bone marrow mesenchymal stromal cells (BM-MSCs). In contrast to pure Mg(OH)2 or AS, cell viability and proliferation were not impaired by Mg(OH)2-AS. Cell morphology remained unchanged upon media supplementation with Mg(OH)2-AS. Preliminary results further indicate enhanced osteogenic differentiation of BM-MSCs in media supplied with ascorbic acid, {beta}-glycerophosphate and dexamethasone and addition of Mg(OH)2-AS. These findings motivate further research towards the inclusion of the material in implants for bone fracture healing.

pharmacology and toxicology↗

bioRxiv2023

Glycan strand cleavage by a lytic transglycosylase, MltD contributes to the expansion of peptidoglycan in Escherichia coli

Peptidoglycan (PG) is a protective sac-like exoskeleton present in most bacterial cell walls. It is a large, covalently cross-linked mesh-like polymer made up of several glycan strands cross-bridged to each other by short peptide chains. Because PG forms a continuous mesh around the bacterial cytoplasmic membrane, opening the mesh is critical to generate space for the incorporation of new material during its expansion. In Escherichia coli, the space-making activity is known to be achieved by cleavage of cross-links between the glycan strands by a set of redundant PG endopeptidases whose absence leads to rapid lysis and cell death. Here, we demonstrate a hitherto unknown role of glycan strand cleavage in making space for cell wall expansion in E. coli. We find that overexpression of a membrane-bound lytic transglycosylase, MltD that cuts the glycan polymers of the PG sacculus rescues the cell lysis caused by the absence of essential cross-link specific endopeptidases, MepS, MepM and MepH. Further detailed genetic and biochemical analysis revealed that MltD works in conjunction with cross-link specific endopeptidases to expand the PG sacculus. Interestingly, we find that cellular MltD levels are stringently controlled by two independent regulatory pathways. MltD undergoes regulated proteolysis by NlpI-Prc, a periplasmic adaptor-protease complex that specifically degrades two of the elongation-specific endopeptidases, MepS and MepH. In addition, MltD levels are post-transcriptionally controlled by RpoS, a stationary-phase specific sigma factor. Overall, our results show that coordinated cleavage of the glycan strands and the peptide cross-bridges facilitates the opening of the PG mesh for successful expansion of the cell wall during growth of a bacterium. AUTHOR SUMMARYMost bacteria are protected by a cell wall made up of peptidoglycan (PG), a mesh-like large polymer. PG consists of several linear glycan strands interlinked through short peptide chains to form a continuous meshwork around the bacterial cytoplasmic membrane. Because PG tightly encases the cytoplasmic membrane, the growth of a bacterial cell is coupled to the expansion of PG requiring the activity of hydrolytic enzymes that cleave PG cross-links to make space for incorporation of new PG material. ln E. coli, a set of redundant cross-link specific endopeptidases are known to be crucial for expansion of PG. In this study, we show that cleavage of the glycan polymers by MltD, a glycan cleaving enzyme compensates the absence of cross-link cleavage and contributes to the expansion of PG. Overall, our work shows a previously unknown role of glycan hydrolases in cell wall expansion identifying these as potential targets for development of cell wall-specific antimicrobial agents.

microbiology↗

bioRxiv2023

Engineered autocrine signaling eliminates muscle cell FGF2 requirements for cultured meat production

Cultured meat is a promising technology that faces substantial cost barriers which are currently driven largely by the price of media components. Growth factors such as fibroblast growth factor 2 (FGF2) drive the cost of serum-free media for relevant cells including muscle satellite cells. Here, we engineered immortalized bovine satellite cells (iBSCs) for inducible expression of FGF2 and/or mutated RasG12V in order to overcome media growth factor requirements through autocrine signaling. Engineered cells were able to proliferate over multiple passages in FGF2-free medium, thereby eliminating the need for this costly component. Additionally, cells maintained their myogenicity, albeit with reduced differentiation capacity. Ultimately, this offers a proof-of-principle for lower-cost cultured meat production through cell line engineering.

bioengineering↗

bioRxiv2020

HIV-1 gp120 impairs spatial memory through CREB

HIV-associated neurocognitive disorders (HAND) remains an unsolved problem in the clinical management of HIV-1 carriers, because existing anti-retroviral therapy while suppressing viral replication, do not prevent neurocognitive impairment (e.g. spatial memory loss). HIV-1 gp120 protein has been proposed to contribute to HAND because it is shed by infected cells and the use of antibodies revealed its presence in cerebrospinal fluid (CSF) even in the combinatory antiretroviral therapy (cART) era. The cyclic AMP response element-binding protein (CREB) has long been known to be a star player in memory. CREB exerts its effect partially through regulating the genes for peroxisome proliferator-activated receptor gamma coactivator (PGC)-1 and brain-derived neurotrophic factor (BDNF). CREB, PGC-1, and BDNF levels are low in the brains of patients with neurodegenerative diseases and a dearth of either protein is associated with cognitive decline. We have obtained data showing that gp120 contributes to neurodegeneration by altering CREB phosphorylation on serine residue 133 thus disrupting mitochondrial movement and synaptic plasticity leading to spatial memory loss. Inhibition of CREB function was also associated with a decrease of ATP levels and lower mitochondrial DNA copy numbers. Our data was validated in vitro (primary mouse neurons and neuronal cell line, SH-SY5Y) and in vivo (gp120-tg mice and mice injected with gp120). The negative effect of gp120 was alleviated in cells and animals in the presence of Rolipram. Hence, we conclude that HIV-1 gp120 protein contributes to spatial memory impairment via inhibition of CREB protein activity.

neuroscience↗