Biology subjects

Tavakoli, M.

Publications and source records attributed to Tavakoli, M..

7 recordsLinked to original sources

bioRxiv2026

Transient ATR inhibition following ionizing radiation enhances immune-mediated antitumor response and survival

BackgroundATR activation following DNA damage from cancer treatments such as radiation can mitigate anticancer efficacy, making ATR inhibitors (ATRi) an attractive therapeutic. In vivo and in vitro studies have shown enhanced tumor cell radiosensitivity with the ATRi ceralasertib, elimusertib, and berzosertib, however, the potentiating effect of ATRi on ionizing radiation (IR) through immune-based mechanisms has only been studied with ceralasertib. MethodsWe aimed to determine if antitumor immune responses observed with ceralasertib in combination with IR extend to the other ATRi class members in the preclinical CT26 mouse model. We also examined the relationship between exposure and immune stimulation, efficacy and survival outcomes of each ATRi when combined with IR. ResultsCeralasertib and elimusertib, not berzosertib, synergized with IR in a dose and schedule-dependent manner to modify tumor antigen-specific CD8+ T cell populations in the draining lymph node. Transient ATRi therapy, combined with IR, enhances antitumor efficacy, promoted tumor shrinkage, and increased survival. ATRi elicited differential inflammatory gene induction and dose-dependent unique cytotoxicity profiles in vitro. ConclusionThe immune mediated antitumor effect of ATRi combined with radiation is dose and schedule dependent, and while likely a class effect, may differ between ATRi compounds.

cancer biology↗

bioRxiv2024

Platelet Membrane-Coated SPION for Targeted Paclitaxel Delivery and Magnetic Hyperthermia in Cancer Therapy

Due to the limited therapeutic efficacy and side effects associated with conventional chemotherapy, researchers have turned their attention to developing targeted drug delivery systems using advanced nanotechnology. Coating nanoparticles (NPs) with cell membranes is a promising strategy because it extends their circulation times and allows them to selectively adhere to damaged vessel sites through the platelet membrane surface, thereby enhancing tumor uptake. Herein, we have developed a biomimetic drug delivery system consisting of superparamagnetic iron oxide nanoparticles (SPIONs) coated by platelet membranes (PM) for carrying Paclitaxel (PTX) to exploit the synergism effect of chemotherapy and magnetic hyperthermia. Controlled-release PTX nanoparticles exhibited consistent behavior over time, indicating no significant difference in release between SPION/PTX and SPION/PTX/PM at pH 7.4. However, at pH 5.5, improved release was observed, specifically a 1.4-fold increase for SPION/PTX/PM. The confocal and flow cytometry results show an enhancement in the cellular uptake of SPION/PTX/PM nanoparticles, with an average fluorescence intensity of 142 {+/-}12.5. MTT results indicated that SPION/PTX/PM demonstrates superior cytotoxic effects compared to SPION/PTX and PTX alone, showing an IC50 value of 5 g/mL after 48 h of treatment. Furthermore, the IC50 decreased to 1 g/mL when an alternating magnetic field was applied. Hence, the in vivo results and histopathological staining showed that the SPION/PTX/PM-AFM treatment group exhibited the highest rate of tumor growth inhibition, reaching nearly 92.14 %. These findings highlight the potential of using platelet membrane-coated nanoparticles for targeted delivery, combining magnetic hyperthermia and chemotherapy to minimize chemotherapys undesirable effects while maximizing therapeutic outcomes.

bioengineering↗

bioRxiv2024

niiv: Fast Self-supervised Neural ImplicitIsotropic Volume Reconstruction

Three-dimensional (3D) microscopy data often is anisotropic with significantly lower resolution (up to 8x) along the z axis than along the xy axes. Computationally generating plausible isotropic resolution from anisotropic imaging data would benefit the visual analysis of large-scale volumes. This paper proposes niiv, a self-supervised method for isotropic reconstruction of 3D microscopy data that can quickly produce images at arbitrary output resolutions. The representation embeds a learned latent code within a neural field that describes the implicit higher-resolution isotropic image region. We use a novel attention-guided latent interpolation approach, which allows flexible information exchange over a local latent neighborhood. Under isotropic volume assumptions, we self-supervise this representation on low-/high-resolution lateral image pairs to reconstruct an isotropic volume from low-resolution axial images. We evaluate our method on simulated and real anisotropic electron (EM) and light microscopy (LM) data. Compared to a state-of-the- art diffusion-based method, niiv shows improved reconstruction quality (+1 dB PSNR) and is over three orders of magnitude faster (1,000x) to infer. Specifically, niiv reconstructs a 1283 voxel volume in 2/10th of a second, renderable at varying (continuous) high resolutions for display.

bioinformatics↗

bioRxiv2023

Brain network analysis in Parkinson's disease patients based on graph theory

Development of Parkinsons disease causes functional impairment in the brain network of Parkinsons patients. The aim of this study is to analyze brain networks of people with Parkinsons disease based on higher resolution parcellations and newer graphical features. The topological features of brain networks were investigated in Parkinsons patients (19 individuals) compared to healthy individuals (17 individuals) using graph theory. In addition, four different methods were used in graph formation to detect linear and nonlinear relationships between functional magnetic resonance imaging (fMRI) signals. The functional connectivity between the left precuneus and the left amygdala, as well as between the vermis 1-2 and the left temporal lobe was evaluated for the healthy and the patient groups. The difference between the healthy and patient groups was evaluated by non-parametric t-test and U-test. Based on the results, Parkinsons patients showed a significant decrease in centrality criterion compared to healthy subjects. Furtheremore, changes in regional features of brain network were observed. There was also a significant difference between the two groups of healthy subjects and Parkinsons patients in different areas by applying centrality criterion and the correlation coefficients. The results obtained for topological features indicate changes in the functional brain network of Parkinsons patients. Finally, similar areas obtained by all three methods of graph formation in the evaluation of connectivity between paired regions in the brain network of Parkinsons patients increased the reliability of the results.

neuroscience↗

bioRxiv2021

ISL1 is an essential determinant of structural and functional tonotopic representation of sound

A cardinal feature of the auditory pathway is frequency selectivity, represented in a tonotopic map from the cochlea to the cortex. The molecular determinants of the auditory frequency map are unknown. Here, we discovered that the transcription factor ISL1 regulates the molecular and cellular features of auditory neurons, including the formation of the spiral ganglion and peripheral and central processes that shape the tonotopic representation of the auditory map. We selectively knocked out Isl1 in auditory neurons using Neurod1Cre strategies. In the absence of Isl1, spiral ganglion neurons migrate into the central cochlea and beyond, and the cochlear wiring is profoundly reduced and disrupted. The central axons of Isl1 mutants lose their topographic projections and segregation at the cochlear nucleus. Transcriptome analysis of spiral ganglion neurons shows that Isl1 regulates neurogenesis, axonogenesis, migration, neurotransmission-related machinery, and synaptic communication patterns. We show that peripheral disorganization in the cochlea affects the physiological properties of hearing in the midbrain and auditory behavior. Surprisingly, auditory processing features are preserved despite the significant hearing impairment, revealing central auditory pathway resilience and plasticity in Isl1 mutant mice. Mutant mice have a reduced acoustic startle reflex, altered prepulse inhibition, and characteristics of compensatory neural hyperactivity centrally. Our findings show that ISL1 is one of the obligatory factors required to sculpt auditory structural and functional tonotopic maps. Still, upon Isl1 deletion, the ensuing central compensatory plasticity of the auditory pathway does not suffice to overcome developmentally induced peripheral dysfunction of the cochlea.

neuroscience↗

bioRxiv2020

Direct Photon-by-photon Analysis of Time-Resolved Pulsed Excitation Data using Bayesian Nonparametrics

Lifetimes of chemical species are typically estimated, across each illuminated spot of a sample, by either fitting time correlated single photon counting (TCSPC) decay histograms or, more recently, through phasor analysis from time-resolved photon arrivals. While both methods yield lifetimes in a computationally efficient manner, the performance of both methods is limited by the choices made when fitting a TCSPC histogram. In addition, phasor analysis also requires setting the number of chemical species by hand before lifetimes can be determined. Yet the number of species itself is encoded in the photon arrival times collected for each illuminated spot and need not be set by hand a priori. Here we propose a direct photo-by-photon analysis of data drawn from pulsed excitation experiments to infer, simultaneously and self-consistently, the number of species and their associated lifetimes from as little as a few thousand photons for two species. We do so by leveraging new mathematical tools within the Bayesian nonparametric (BNP) paradigm that we have previously exploited in the analysis of single photon arrivals from single spot confocal microscopy. We benchmark our method on simulated as well as experimental data for one, two, three, and four species with data sets from both immobilized and freely diffusing molecules at the level of one illuminated spot. SUMMARYPhoton arrivals obtained from fluorescence experiments encode not only the lifetimes of chemical species but also the number of chemical species involved in the experiment. Traditional methods of analysis, such as phasor methods and methods relying on maximum likelihood or (parametric) Bayesian analysis of photon arrivals or photon arrival histograms of TCSPC data, must first ascertain the number of chemical species separately and, once specified, determine their associated lifetimes. Here we develop a method to learn the number of fluorescence species and their associated lifetimes simultaneously. We achieve this by exploiting Bayesian nonparametrics. We benchmark our approach on both simulated and experimental data for one species and mixtures of two to four species.

biophysics↗

bioRxiv2019

Pitching single focus confocal data analysis one photon at a time with Bayesian nonparametrics

Fluorescence time traces are used to report on dynamical properties of molecules. The basic unit of information in these traces is the arrival time of individual photons, which carry instantaneous information from the molecule, from which they are emitted, to the detector on timescales as fast as microseconds. Thus, it is theoretically possible to monitor molecular dynamics at such timescales from traces containing only a sufficient number of photon arrivals. In practice, however, traces are stochastic and in order to deduce dynamical information through traditional means-such as fluorescence correlation spectroscopy (FCS) and related techniques-they are collected and temporally autocorrelated over several minutes. So far, it has been impossible to analyze dynamical properties of molecules on timescales approaching data acquisition without collecting long traces under the strong assumption of stationarity of the process under observation or assumptions required for the analytic derivation of a correlation function. To avoid these assumptions, we would otherwise need to estimate the instantaneous number of molecules emitting photons and their positions within the confocal volume. As the number of molecules in a typical experiment is unknown, this problem demands that we abandon the conventional analysis paradigm. Here, we exploit Bayesian nonparametrics that allow us to obtain, in a principled fashion, estimates of the same quantities as FCS but from the direct analysis of traces of photon arrivals that are significantly smaller in size, or total duration, than those required by FCS.

biophysics↗