Biology subjects

Kalantari, A.

Publications and source records attributed to Kalantari, A..

8 recordsLinked to original sources

bioRxiv2026

Digital-twin optimized transcranial temporal interference electrical stimulation alters rat brain activity patterns and metabolism including deep structures

Non-invasive deep-brain stimulation (DBS) using transcranial alternating current stimulation (tACS) with temporal interference (TI) has emerged as a promising approach for therapeutic applications in motor and neuropsychiatric disorders. Here, we present a preclinical TI tACS protocol for adult rats that follows a systems approach: an anatomically realistic finite-element digital twin of the rat head is used to optimize electrode placement and injected currents for a deep target, and the model predictions are then tested in vivo. We combine, minimal invasive TI tACS with functional MRI (fMRI) to characterize stimulation-related brain-wide neural responses, alterations in functional connectivity, and changes in neurotransmitter levels. The optimized montage targeted in particular the ventral (motor-related) thalamus. Stimulation-evoked fMRI revealed robust bilateral activation across both subcortical and cortical regions, such as the thalamus, hippocampus, amygdala, retrosplenial and anterior cingulate cortex, which, in turn, reflects direct and indirect activations of brain circuitries by TI tACS. Changes in the connectivity patterns during resting-state fMRI were limited (e.g., fimbria of the hippocampus), but partially overlapped with regional stimulation-evoked fMRI. Therefore, we assume only a short-term influence of TI on neural networks following a single stimulation. MR spectroscopy indicated a trend towards an increased glutamate/GABA ratio in the thalamus. Overall, we demonstrate that TI is a feasible and effective approach for non-invasive DBS in rodents, and that digital twin-based optimization combined with in vivo validation provides a workflow towards individualized stimulation and a foundation for future mechanistic and translational studies in disease models.

neuroscience↗

bioRxiv2026

A harmonized phantom MRI quality control framework identifies sources of longitudinal and multi-site variability

The shift towards open science in preclinical research requires high-quality, comparable data adhering to FAIR principles, yet rigorous quality assurance (QA) and quality control (QC) frameworks remain less established in preclinical magnetic resonance imaging (MRI) than in clinical imaging. To address this limitation, a multicenter study was conducted across 21 international laboratories using standardized commercial liquid phantoms for mouse and rat MRI setups and a harmonized acquisition protocol. Data processing was centralized using AIDAqc, an automated pipeline extracting quantitative metrics including signal-to-noise ratio (SNR), temporal SNR (tSNR), ghost-to-signal ratio (GSR), and motion-equivalent temporal instability, combined with five complementary outlier-detection algorithms. The evaluated datasets encompassed magnetic field strengths from 3.0 to 16.4 T and heterogeneous coil and acquisition configurations. In mouse phantom data, SNR and tSNR were significantly lower at 3 T than at 7 and 9.4 T, whereas artifact-related metrics did not differ significantly between field-strength groups. In rat phantom data, differences between field strengths were less pronounced. At 7 T, substantial dataset-specific differences were observed in anatomical and functional quality metrics, also among datasets using the similar coil configuration. Multicenter reference values for frequently represented 7 T configurations were established, including SNR/tSNR of 48 {+/-} 3/48 {+/-} 1 dB for mouse surface-coil datasets and 49 {+/-} 3/44 {+/-} 4 dB for rat array-coil datasets. Longitudinal anatomical SNR showed generally low variability, whereas ghosting was more variable across time. Automated outlier detection additionally identified transient acquisition instabilities that were not always apparent by visual inspection. Together, these findings show that field strength and nominal coil configuration alone do not adequately characterize MRI performance and support standardized, longitudinal phantom-based QC combined with automated analysis as a practical approach for improving the reliability, transparency, and interoperability of multicenter preclinical MRI data.

bioengineering↗

bioRxiv2026

ENS lineage potential is not intrinsically regionalized but is modulated by PTPRZ1 signaling

The enteric nervous system (ENS) orchestrates critical gastrointestinal functions including peristalsis, fluid exchange, and blood flow regulation, and develops from vagal neural crest (vNC) progenitors that colonize the gut. While the gut epithelium and mesenchyme exhibit pronounced anterior-posterior (A-P) transcriptional patterning and lineage diversification after mid-gestation, whether the ENS itself undergoes comparable regional embryonic transcriptional diversification has remained unclear. Here, we use multiplexed single-cell RNA sequencing and functional perturbations to dissect how the ENS is patterned between E13.5 and E18.5 within the context of a regionally specialized gut. We find that, while the epithelium and mesenchyme display strong and enduring AP-graded gene expression programs, the ENS lacks intrinsic regionalization and instead follows a predominantly temporal maturation trajectory characterized by neuronal and glial differentiation states. Integrative ligand-receptor analyses reveal that mesenchymal populations express A-P patterned microenvironmental cues that correlate with subtle, region-linked transcriptional tuning in ENS cells, despite the absence of intrinsic A-P identities. Among these signals, PTN/MDK-PTPRZ1 signaling emerges as a major spatial and temporal input to the ENS, with gradients that track both small intestinal region and developmental time. To test the relevance of PTPRZ1 signaling for human ENS development, we perturbed pluripotent stem cell-derived ENS cultures and found that modulating PTPRZ1 signaling impacts proliferative, neurogenic, and neurotransmitter-specification programs, confirming that niche-derived cues fine-tune ENS development. Together, our findings support a model in which the small intestine establishes A-P regionalization through epithelial and mesenchymal patterning, whereas the ENS maintains a relatively uniform core neuroglial program that is secondarily refined by localized microenvironmental signals. This framework highlights how extrinsic, region-specific cues, rather than intrinsic regional transcriptional codes, shape ENS maturation within the small intestine.

developmental biology↗

bioRxiv2024

Proportional recovery in mice with cortical stroke

The proportional Recovery Rule (PRR) has been frequently used to predict recovery of lost motor function in acute stroke patients. However, it still needs to be explored whether the same concept applies to preclinical, i.e. animal models of stroke recovery. To address this question, we investigated behavioral data from 125 adult male C57Bl/6J mice with photothrombotic strokes in the sensorimotor cortex. Lesion size and location were determined in the first week using in vivo T2-weighted MRI. Motor recovery was evaluated repeatedly over four weeks using the cylinder, grid walk, and rotating beam test. Recovery trajectories were analyzed using a newly formulated Mouse Recovery Rule (MRR), comparing it against the traditional PRR. Initial findings indicated variable recovery patterns, which were separated using a stepwise linear regression approach resulting in two clusters: 47% PRR and 53% MRR. No significant correlation was found between recovery patterns and lesion size or location, suggesting that other biological factors drive individual differences in recovery. Of note, in the MRR cluster, animals recovered to 90% of their initial behavioral state within the first four weeks post-stroke, which is higher than the 70% recovery usually reported in human PRR studies. This study demonstrates the complexity of translating the PRR to stroke recovery models in mice and underscores the need for species-specific recovery models. Our findings have implications for designing and interpreting therapeutic strategies for stroke recovery in preclinical settings, with the potential to improve the predictive accuracy of stroke recovery assessments.

animal behavior and cognition↗

bioRxiv2023

Patterning and folding of intestinal villi by active mesenchymal dewetting

Tissue folding generates structural motifs critical to organ function. In the intestine, bending of a flat epithelium into a periodic pattern of folds gives rise to villi, the numerous finger-like protrusions that are essential for nutrient absorption. However, the molecular and mechanical mechanisms driving the initiation and morphogenesis of villi remain a matter of debate. Here, we identify an active mechanical mechanism that simultaneously patterns and folds intestinal villi. We find that PDGFRA+ subepithelial mesenchymal cells generate myosin II-dependent forces sufficient to produce patterned curvature in neighboring tissue interfaces. At the cell-level, this occurs through a process dependent upon matrix metalloproteinase-mediated tissue fluidization and altered cell-ECM adhesion. By combining computational models with in vivo experiments, we reveal these cellular features manifest at the tissue-level as differences in interfacial tensions that promote mesenchymal aggregation and interface bending through a process analogous to the active de-wetting of a thin liquid film.

developmental biology↗

bioRxiv2022

Formulation of FMD vaccine in Naloxone/Alum mixture: A potency study

BackgroundCurrent Foot-and-Mouth disease (FMD) vaccines are commonly formulated in the alum adjuvant. Several studies showed that this form of vaccine, although able to control the infection, lacks the ability to eradicate the infection completely. ObjectivesIn this study, the FMD vaccine was formulated in a naloxone/alum mixture as an adjuvant, and its potency was compared with the alum-formulated vaccine. MethodsExperimental Balb/c mice were immunized with a commercial vaccine or naloxone/alum-based vaccine two times, subcutaneously at two-week intervals. Lymphocyte proliferation was assessed using BrdU, and IL-4, IFN-{gamma}, and TNF- cytokines, specific total IgG as well as IgG1/IgG2a were evaluated by ELISA. In addition, the gene expression profiles of IL-12, IL-17, and IFN-{gamma} cytokines were determined by real-time PCR. ResultsResults showed that mice immunized with the FMD vaccine formulated with the naloxone/alum mixture exhibited a tiny increase in the production of IFN-{gamma} and TNF- cytokines compared to the routine vaccine. However, mice immunized with the FMD vaccine formulated with the naloxone/alum mixture revealed a significant increase in the expression of IL-12, IL-17, and IFN-{gamma} cytokines compared to those immunized with the routine vaccine. In addition, the novel formulation led to increased production of specific total IgG in comparison with the routine vaccine. ConclusionsOur findings suggest that naloxone formulated in the FMD vaccine could improve cellular and humoral immune responses. However, the effect of this formulation on the efficacy of vaccine is remained to be clarified in future studies.

molecular biology↗

bioRxiv2022

hPSC-Derived Enteric Ganglioids Model Human ENS Development and Function

The enteric nervous system (ENS) plays a central role in gut physiology and mediating the crosstalk between the gastrointestinal (GI) tract and other organs. The human ENS has remained elusive, highlighting the need for an in vitro modeling and mapping blueprint. Here we map out the developmental and functional features of the human ENS, by establishing robust and scalable 2D ENS cultures and 3D enteric ganglioids from human pluripotent stem cells (hPSCs). These models recapitulate the remarkable neuronal and glial diversity found in primary tissue and enable comprehensive molecular analyses that uncover functional and developmental relationships within these lineages. As a salient example of the power of this system, we performed in-depth characterization of enteric nitrergic neurons (NO neurons) which are implicated in a wide range of GI motility disorders. We conducted an unbiased screen and identified drug candidates that modulate the activity of NO neurons and demonstrated their potential in promoting motility in mouse colonic tissue ex vivo. We established a high-throughput strategy to define the developmental programs involved in NO neuron specification and discovered that PDGFR inhibition boosts the induction of NO neurons in enteric ganglioids. Transplantation of these ganglioids in the colon of NO neuron-deficient mice results in extensive tissue engraftment, providing a xenograft model for the study of human ENS in vivo and the development of cell-based therapies for neurodegenerative GI disorders. These studies provide a framework for deciphering fundamental features of the human ENS and designing effective strategies to treat enteric neuropathies.

developmental biology↗

bioRxiv2020

Androgen regulates SARS-CoV-2 receptor levels and is associated with severe COVID-19 symptoms in men

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has led to a global health crisis, and yet our understanding of the disease pathophysiology and potential treatment options remains limited. SARS-CoV-2 infection occurs through binding and internalization of the viral spike protein to angiotensin converting enzyme 2 (ACE2) on the host cell membrane. Lethal complications are caused by damage and failure of vital organs that express high levels of ACE2, including the lungs, the heart and the kidneys. Here, we established a high-throughput drug screening strategy to identify therapeutic candidates that reduce ACE2 levels in human embryonic stem cell (hESC) derived cardiac cells. Drug target analysis of validated hit compounds, including 5 alpha reductase inhibitors, revealed androgen signaling as a key modulator of ACE2 levels. Treatment with the 5 alpha reductase inhibitor dutasteride reduced ACE2 levels and internalization of recombinant spike receptor binding domain (Spike-RBD) in hESC-derived cardiac cells and human alveolar epithelial cells. Finally, clinical data on coronavirus disease 2019 (COVID-19) patients demonstrated that abnormal androgen states are significantly associated with severe disease complications and cardiac injury as measured by blood troponin T levels. These findings provide important insights on the mechanism of increased disease susceptibility in male COVID-19 patients and identify androgen receptor inhibition as a potential therapeutic strategy.

cell biology↗