Biology subjects

Soltani, M.

Publications and source records attributed to Soltani, M..

6 recordsLinked to original sources

bioRxiv2025

Hypergraph Neural Networks Reveal Spatial Domains from Single-cell Transcriptomics Data

I.Spatial transcriptomics enables the measurement of gene expression while preserving spatial context within tissue samples. A key challenge is detecting spatial domains of biologically meaningful cell clusters, typically addressed using graph-based models like SpaGCN and STAGATE. However, these methods only capture pairwise relationships and fail to model complex higher-order interactions. We propose a hypergraph-based framework for spatial transcriptomics using Hypergraph Neural Networks (HGNNs). Our approach constructs hyperedges from top-K densest overlapping subgraphs and integrates histological image features and gene expression profiles. Combined with autoencoders, our model effectively learns expressive node embeddings in an unsupervised setting. Evaluated on a mouse brain dataset, our model achieves the highest iLISI score of 1.843 and outperforms state-of-the-art baselines with an ARI of 0.51 and a Leiden score of 0.60.

bioinformatics↗

bioRxiv2024

Secretion and Periplasmic Activation of a Potent Endonuclease in E. coli

Sm Endonuclease (SmEn) is a promiscuous, highly active nuclease widely used in protein purification, 2D protein gels, and gene and cell therapy. We aimed to recombinantly and economically produce this reagent using E. coli. Despite widespread application of E. coli for recombinant production of proteins, cytoplasmic expression of this protein resulted in no activity accumulation. We therefore investigated translocation of SmEn to the periplasm of E. coli by evaluating several signal sequences, E. coli host cells, and incubation conditions. For rapid feedback, we developed a crude lysate-based nuclease activity assay that enabled convenient screening and identified suitable conditions for active SmEn accumulation. Signal sequence selection was most influential with additional benefit gained by slowing synthesis either using the transcriptionally weakened strain, C43 (DE3) or by reducing incubation temperature. While our study provides valuable insights for optimizing a nuclease translocation and reducing production costs, more research is needed to explore the influence of mRNA secondary structure at the translation initiation region on protein expression and translocation. Overall, our rapid screening assay facilitated the development of an effective production process for a protein with potential cytoplasmic toxicity as well as the need of disulfide bond formation.

systems biology↗

bioRxiv2022

Targeted Nano Sized Drug Delivery to Heterogeneous Solid Tumor Microvasculatures: Implications for Immunoliposomes Exhibiting Bystander Killing Effect

Targeted drug delivery to cancer cells utilizing antibodies against oncogenic cell-surface receptors is an emerging therapeutical approach. Here, we developed a computational framework to evaluate the treatment efficacy of free Doxorubicin (Dox) and immunoliposome at different stages of vascular solid tumors. Firstly, three stages of vascularized tumors with different microvascular densities (MVDs) are generated using mathematical modeling of tumor-induced angiogenesis. Secondly, the fluid flow in vascular and interstitial spaces is calculated. Ultimately, convection-diffusion-reaction equations governing on classical chemotherapy (stand-alone Dox) and immunochemotherapy (drug-loaded nanoparticles) are separately solved to calculate the spatiotemporal concentrations of different therapeutic agents. The present model considers the key processes in targeted drug delivery, including association/disassociation of payloads to cell receptors, cellular internalization, linker cleavage, intracellular drug release, and bystander-killing effect. Our results show that reducing MVD decreases the interstitial fluid pressure, allowing higher rates of the drug to enter the tumor microenvironment. Also, immunoliposomes exhibiting bystander-killing effect yield higher drug internalization, which supports a higher intracellular Dox concentration during immunochemotherapy. Bystander-killing effect alongside intracellular Dox release and persistence of immunoliposomes within tumor over a longer period lead to more homogeneous drug distribution and a much greater fraction of killed cancer cells than classical chemotherapy. Our findings also demonstrate drug transport at tumor microvascular networks is increased by decreasing MVD, leading to better treatment outcomes. Present results can be used to improve the treatment efficacy of drug delivery at different stages of vascular tumors.

bioengineering↗

bioRxiv2022

Charge neutralization of the active site glutamates does not limit substrate binding and transport by EmrE

EmrE, a small multidrug resistance (SMR) transporter from E. coli, confers broad-spectrum resistance to polyaromatic cations and quaternary ammonium compounds. Previous transport assays demonstrate that EmrE transports a +1 and a +2 substrate with the same stoichiometry of 2 protons:1 cationic substrate. This suggests that EmrE substrate binding capacity is limited to neutralization of the two essential glutamates, E14A and E14B (one from each subunit in the antiparallel homodimer), in the primary binding site. Here we explicitly test this hypothesis, since EmrE has repeatedly broken expectations for membrane protein structure and transport mechanism. We previously showed that EmrE can bind a +1 cationic substrate and proton simultaneously, with cationic substrate strongly associated with one E14 residue while the other remains accessible to bind and transport a proton. Here we demonstrate that EmrE can bind a +2 cation substrate and a proton simultaneously using NMR pH titrations of EmrE saturated with divalent substrates, for a net +1 charge in the transport pore. Further, we find that EmrE can alternate access and transport a +2 substrate and proton at the same time. Together, these results lead us to conclude that E14 charge neutralization does not limit the binding and transport capacity of EmrE.

biophysics↗

bioRxiv2021

Amplification and attenuation of noisy expression by export processes

Inside mammalian cells, single genes are known to be transcribed in stochastic bursts leading to the synthesis of nuclear RNAs that are subsequently exported to the cytoplasm to create mRNAs. We systematically characterize the role of export processes in shaping the extent of random fluctuations (i.e. noise) in the mRNA level of a given gene. Using the method of Partitioning of Poisson arrivals, we derive an exact analytical expression for the noise in mRNA level assuming that the nuclear retention time of each RNA is an independent and identically distributed random variable following an arbitrary distribution. These results confirm recent experimental/theoretical findings that decreasing the nuclear export rate buffers the noise in mRNA level, and counterintuitively, decreasing the noise in the nuclear retention time enhances the noise in the mRNA level. Next, we further generalize the model to consider a dynamic extrinsic disturbance that affects the nuclear-to-cytoplasm export. Our results show that noise in the mRNA level varies non-monotonically with the disturbance timescale. More specifically, high- and low-frequency external disturbances have little impact on the mRNA noise level, while noise is amplified at intermediate frequencies. In summary, our results systematically uncover how the coupling of bursty transcription with nuclear export can both attenuate or amplify noise in mRNA levels depending on the nuclear retention time distribution and the presence of extrinsic fluctuations.

systems biology↗

bioRxiv2019

Enhancement of gene expression noise due to nonspecific transcription factor binding

The genome contains several high-affinity non-functional binding sites for transcription factors (TFs) creating a hidden and unexplored layer of gene regulation. We investigate the role of such "decoy sites" in controlling noise (random fluctuations) in the level of a TF that is synthesized in stochastic bursts. Prior studies have assumed that decoy-bound TFs are protected from degradation, and in this case decoys function to buffer noise. Relaxing this assumption to consider arbitrary degradation rates for both bound/unbound TF states, we find rich noise behaviors. For low-affinity decoys, noise in the level of unbound TF always monotonically decreases to the Poisson limit with increasing decoy numbers. In contrast, for high affinity decoys, noise levels first increase with increasing decoy numbers, before decreasing back to the Poisson limit. Interestingly, while protection of bound TFs from degradation slows the time-scale of fluctuations in the unbound TF levels, decay of bounds TFs leads to faster fluctuations and smaller noise propagation to downstream target proteins. In summary, our analysis reveals stochastic dynamics emerging from nonspecific binding of TFs, and highlight the dual role of decoys as attenuators or amplifiers of gene expression noise depending on their binding affinity and stability of the bound TF.

systems biology↗