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DOE OSTI2020

Inhibition of PTEN activity promotes IB4‐positive sensory neuronal axon growth

Abstract Traumatic nerve injuries have become a common clinical problem, and axon regeneration is a critical process in the successful functional recovery of the injured nervous system. In this study, we found that peripheral axotomy reduces PTEN expression in adult sensory neurons; however, it did not alter the expression level of PTEN in IB4‐positive sensory neurons. Additionally, our results indicate that the artificial inhibition of PTEN markedly promotes adult sensory axon regeneration, including IB4‐positive neuronal axon growth. Thus, our results provide strong evidence that PTEN is a prominent repressor of adult sensory axon regeneration, especially in IB4‐positive neurons.

Zhou, Li‐Yu↗

DOE OSTI2022

Cold acclimation threshold induction temperatures of switchgrass ecotypes grown under a long and short photoperiod

Abstract Plants can cold acclimate to enhance their freezing tolerance by sensing declining temperature and photoperiod cues. However, the factors influencing genotypic variation in the induction of cold acclimation are poorly understood among perennial grasses. We hypothesized that the more northern upland switchgrass ( Panicum virgatum L.) ecotype develops a higher degree of freezing tolerance by initiating cold acclimation at higher temperatures as compared with the coastal and southern lowland ecotypes. First, we determined the optimal method for assessing freezing tolerance and the length of exposure to 8/4°C required to induce the maximum level of freezing tolerance in the most northern upland and most southern lowland genotypes. We characterized the maximum freezing tolerance of eight uplands, three coastal and five lowland genotypes grown for 21 days at 8/4°C and a 10 or 16 h photoperiod. Next, we identified the temperature required to induce cold acclimation by exposing the 16 genotypes for 7 days at 20–6°C constant temperatures under a 10 or 16 h photoperiod. Cold acclimation initiated at temperatures 5 and 7°C higher in upland than in coastal and lowland genotypes. Among upland genotypes the shorter photoperiod induced cold acclimation at a 1°C higher temperature. Genotypes originating from a more northern latitude initiate cold acclimation at higher temperatures and develop higher maximum freezing tolerances. An earlier response to declining temperatures may provide the upland ecotype with additional time to prepare for winter and provide an advantage when plants are subjected to the rapid changes in fall temperature associated with injurious frosts.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2025

Reestablishing larval connectivity in an estuarine landscape: the importance of shoreline and subtidal oysters ( Crassostrea virginica ) in a comprehensive oyster restoration program

The decline of oyster reefs in estuaries has resulted from a combination of chronic and acute disturbances. The loss has resulted in decreased yield for the oyster fishery as well as a decline in ecological benefits that has led to increased efforts to restore oyster reefs. The need for scientific guidance in accomplishing these restoration goals has become even more pressing in the northcentral Gulf of Mexico in the wake of injury to oyster reefs resulting from the Deepwater Horizon oil spill. Restoration of both the shallow, marsh-fringing oyster aggregations and the deeper subtidal oyster reefs is necessary. Historically, fringing oysters have been overlooked in the oyster habitat landscape because of their limited commercial value. Here, we use a biophysical transport model to examine the transport and settlement of oyster larvae in known oyster reefs along the coast of the northcentral Gulf of Mexico. The modeling demonstrated that the majority of oyster larvae settle within the embayment (>98%) or sub-basin (>65%) of their origin. Additionally, the model demonstrated the importance of fringing oysters as a source of larvae to re-seed other fringing oysters along marsh edges as well as subtidal oyster reefs. We conclude that networks of reefs, including both fringing oyster habitat and subtidal oyster reefs within sub-basins, are necessary to provide resilience to the population at the sub-basin level. Finally, we conclude that fringing oyster habitat may serve as an archipelago-like network to enhance larval supply and connectivity for oysters throughout the mesosaline portions of estuaries.

ADCIRC↗

DOE OSTI2023

Immune checkpoint analysis of T‐cell responses to pp65 and IE‐1 antigens in end‐stage lung diseases

Abstract Lung transplant (LTX) patients are at high risk of cytomegalovirus (CMV) infection, which is often associated with high mortality and morbidity. Reactivation of CMV causes cell injury due to the cytopathic effect of viral replication and triggering of T cell immunity. The aim of this study was to compare expression of immune checkpoints (ICs) (PD‐1, CTLA‐4, LAG‐3 and TIGIT) in CD4, CD8 and CD56 and activation markers CD137, CD154 and CD69 of end‐stage patients awaiting lung transplant. Eighteen pre‐LTX positive for anti‐CMV IgG titres and 18 healthy subjects were enrolled. IC and activation markers have been evaluated through flow cytometric analysis in HC and pre‐LTX patients. Reactive (QF+) and unreactive (QF−) patients were stratified according to QuantiFERON‐CMV assays. ICs' and activation markers' expression were determined before and after in vitro stimulation with pp‐65 and IE‐1 antigens. Lower expression of PD‐1 was observed in CD4 and CD8 cells of pre‐LTX patients than controls, whereas CTLA4 appeared upregulated in CD56 and CD8 cells. TIGIT is increased on the surface of CD4, CD8 and NK cells after peptide stimulation in QF‐negative patients and PD‐1 is only downregulated after stimulation in the QF‐positive patients. This study provides new evidence of immune dysregulation in patients with end‐stage lung disorders, particularly in relation to immune checkpoint cell biology. The change in QF+ mostly happens on cytotoxic cells NK and CD8, while the changes in QF− were observed in adaptive immune cells, including CD4 and CD8.

Bergantini, Laura↗

DOE OSTI2024

Thinking Beyond the Default User: The Impact of Gender, Stereotypes, and Modality on Interpretation of User Needs

Throughout the mechanical design process, designers, the majority of whom are men, often fail to consider the needs of women, resulting in consequences ranging from inconvenience to increased risk of serious injury or death. Although these biases are well studied in other fields of research, the mechanical design field lacks formal investigation into this phenomenon. In this study, engineering students (n = 301) took a survey in which they read a Persona describing a student makerspace user and a Walkthrough describing the user’s interaction with the makerspace while completing a project. During the Walkthrough, the user encountered various obstacles or Pain Points. Participants were asked to recall and evaluate the Pain Points that the user encountered and then evaluated their perceptions of the makerspace and user. Furthermore, the independent variables under investigation were the gender of the user Persona (woman, gender-neutral, or man), the Walkthrough room case (crafting or woodworking makerspace), and the modality of the Persona and Walkthrough (text- or audio-based). Results showed that participants from the Text-based modality were better able to recall Pain Points compared to participants from the Audio-based modality. Pain Points were assessed as more severe when they impacted women users, potentially stemming from protective paternalism. In addition to finding that the gender of a user impacted the way a task environment was perceived, results confirmed the presence of androcentrism, or “default man” assumptions, in the way designers view end users of unknown gender. Promisingly, providing user Persona information in an audio modality significantly reduced this bias compared to text-based modalities, indicating that providing richer detail in user personas has the capability to reduce gender bias in designers.

cognitive-based design↗

DOE OSTI2025

Dysregulation of lung epithelial cell homeostasis and immunity contributes to Middle East respiratory syndrome coronavirus disease severity

Coronaviruses (CoV) emerge suddenly from animal reservoirs to cause novel diseases in new hosts. Discovered in 2012, the Middle East respiratory syndrome coronavirus (MERS-CoV) is endemic in camels in the Middle East and is continually causing local outbreaks and epidemics. While all three newly emerging human CoVs from the past 20 years (SARS-CoV, SARS-CoV-2, and MERS-CoV) cause respiratory disease, each CoV has unique host interactions that drive differential pathogeneses. To better understand the virus and host interactions driving lethal MERS-CoV infection, we performed a longitudinal multi-omics analysis of sublethal and lethal MERS-CoV infection in mice. Significant differences were observed in body weight loss, virus titers, and acute lung injury among lethal and sub-lethal virus doses. Virus-induced apoptosis of type I and II alveolar epithelial cells suggests that loss or dysregulation of these key cell populations was a major driver of severe disease. Omics analysis suggested differential pathogenesis was multi-factorial with clear differences among innate and adaptive immune pathways as well as those that regulate lung epithelial homeostasis. Infection of mice lacking functional T and B cells showed that adaptive immunity was important in controlling viral replication but also increased pathogenesis. In summary, we provide a high-resolution host response atlas for MERS-CoV infection and disease severity. Multi-omics studies of viral pathogenesis offer a unique opportunity to not only better understand the molecular mechanisms of disease but also to identify genes and pathways that can be exploited for therapeutic intervention all of which is important for our future pandemic preparedness.

MERS-CoV↗

DOE OSTI2026

High-quality Acinetobacter genomes recovered from combat wounds via metagenomic sequencing resemble cultured isolate genomes

The ability to accurately characterize wound pathogens is critical to informing clinical decisions for wound infections with complex treatment requirements. Acinetobacter baumannii is an impactful nosocomial pathogen in combat wounds and civilian hospital-acquired infections. An informed understanding of the phylogenetics and epidemiology of A. baumannii infections in military and civilian environments could guide approaches that improve antibiotic treatment regimens for both military and civilian patients. Whole-genome data for bacterial strains can be difficult to obtain due to challenges in culturing isolates from preserved military specimens. Metagenomic sequencing and assembly create opportunities for genomic analysis of pathogens directly from clinical specimens. The ability to perform comparative analyses between metagenome-derived genomes and culture-derived genomes would support a range of comparative bacterial genomic studies. Wound tissue biopsy and effluent samples from combat injuries were subjected to metagenomic sequencing and assembly. In total, 42 microbial metagenome-assembled genomes (MAGs) were obtained directly from metagenomic sequence data, 36 of which were designated “high” quality. Thirty of these genomes corresponded to Acinetobacter, with 29 mapping specifically to A. baumannii. Other observed genera included Bordetella, Citrobacter, Escherichia, and Pseudomonas. Single-copy and multi-copy orthologs were identified across Acinetobacter MAGs and publicly available isolate genomes derived from military and civilian sources. Both MAG and military isolate genomes were annotated with antimicrobial resistance data, and MAG genomes were statistically comparable to genomes obtained from isolates. Our results highlight the potential of de novo metagenome assembly for enabling high-resolution characterization directly from clinical specimens, thereby improving diagnostic precision, guiding antimicrobial stewardship, and enhancing understanding of pathogen evolution across diverse healthcare and battlefield environments.

Acinetobacter baumannii↗

DOE OSTI2024

Early Detection of Li-Ion Battery Thermal Runaway Using Commercial Diagnostic Technologies

The rate of electric vehicle (EV) adoption, powered by the Li-ion battery, has grown exponentially; largely driven by technological advancements, consumer demand, and global initiatives to reduce carbon emissions. As a result, it is imperative to understand the state of stability (SoS) of the cells inside an EV battery pack. That understanding will enable the warning of or prevention against catastrophic failures that can lead to serious injury or even, loss of life. The present work explores rapid electrochemical impedance spectroscopy (EIS) coupled with gas sensing technology as diagnostics to monitor cells and packs for failure markers. These failure markers can then be used for onboard assessment of SoS. Experimental results explore key changes in single cells and packs undergoing thermal or electrical abuse. Rapid EIS showed longer warning times, followed by VOC sensors, and then H 2 sensors. While rapid EIS gives the longest warning time, with the failure marker often appearing before the cell vents, the reliability of identifying impedance changes in single cells within a pack decreases as the pack complexity increases. This provides empirical evidence to support the significant role that cell packaging and battery engineering intricacies play in monitoring the SoS.

25 ENERGY STORAGE↗

DOE OSTI2022

Identification of therapeutic targets in a murine model of severe exertional heat stroke

Exertional heat stroke (EHS) is a potentially lethal condition resulting from high core body temperatures (T C ) in combination with a systemic inflammatory response syndrome (SIRS) with varying degrees of severity across victims, and limited understanding of the underlying mechanism(s). We established a mouse model of severe EHS to identify mechanisms of hyperthermia/inflammation that may be responsible for organ damage. Mice were forced to run on a motorized wheel in a 37.5°C chamber until loss of consciousness and were either removed immediately (exertional heat injury or EHI; T CMax = 42.4 ± 0.2°C) or remained in the chamber an additional 20 min (EHS; T CMax = 42.5 ± 0.4°C). Exercise control mice (ExC) experienced identical procedures to EHS at 25°C. At 3 h post-EHS, there was evidence for an immune/inflammatory response as elevated blood chemokine [interferon γ-induced protein 10 (IP-10), keratinocytes-derived chemokine (KC), macrophage inflammatory proteins (MIP-1α), MIP-1β, MIP-2] and cytokine [granulocyte colony-stimulating factor (G-CSF), interleukins (IL-10), IL-6] levels peaked and were highest in EHS mice compared with EHI and ExC mice. Immunoblotting of organs susceptible to EHS damage indicated that several kinases were sensitive to stress associated with heat/inflammation and exercise; specifically, phosphorylation of liver c-Jun NH 2 -terminal kinase (JNK) at threonine 183/tyrosine 185 immediately (0 h) postheating related to heat illness severity. We have established a mouse EHS model, and JNK [or its downstream target(s)] could underlie EHS symptomatology, allowing the identification of molecular pathways or countermeasure targets to mitigate heat illness severity, enable complete recovery, and decrease overall EHS-related fatalities.

Physiology↗

DOE OSTI2024

Renal vascular control during normothermia and passive heat stress does not differ between healthy younger men and women

The mechanisms underlying greater heat-induced acute kidney injury risk in men versus women remain unknown. This study examined renal vascular control, including both vasodilatory (oral protein load) and vasoconstrictor (cold presser test) responses, during normothermia and heat stress and compared these responses between men and women. The results indicated that in both conditions neither renal vasodilatory nor vasoconstrictor responses differ between younger men and younger women.

Physiology↗

DOE OSTI2021

The research into the propagation law of the shock wave of a gas explosion inside a building

Based on the dissipation rate conservation equations of turbulent kinetic energy in the k‐ ε turbulence model, a complicated three‐dimensional finite element model of a kitchen filled with gas mixture is developed by using the open source field operation and manipulation (OpenFOAM). Two representative kitchens were used to investigate the propagation law of the shock wave of a gas explosion inside a building by considering the key characteristics of the blast shock wave. The influence of some crucial parameters, such as initial conditions and kitchen parameters, on the properties of the blast shock wave is investigated. The basic steps to predict the peak pressure of the blast shock wave are given in consideration of the initial condition and the kitchen whilst the injury effect of the blast shock wave on the humans and animals is evaluated. The research results indicate that the pressure time history and the peak pressure space distribution are greatly influenced by the kitchen design layout. The coupled interaction between the initial temperature and gas volume concentration, especially at the upper and lower explosion limits of the gas, significantly affects the peak pressure. The peak pressure varies significantly with the opening and the buffer; however, it has little relation with the width, length, and height of the kitchen. The proposed method can accurately and effectively predict the peak pressure of the blast shock wave inside buildings. In terms of the peak pressure space distribution of the explosion shock wave, the peak pressure is much higher than the threshold of the killing pressure, which is unsafe for the humans and animals in the building.

Lin, Shu-Chao↗

DOE OSTI2022

The Study on the Shock Wave Propagation Rule of a Gas Explosion in a Gas Compartment

Combined with the k-ε turbulence model of general application, a refined finite element model of a utility tunnel’s gas compartment filled with the methane/air mixture is developed. A series of analyses are made by using the powerful industry-leading computational fluid dynamics (CFD) software flame acceleration simulator (FLACS) to study the shock wave propagation rule in the gas compartment. The longitudinal and transversal distribution laws of the explosion shock wave are gained taking into consideration the spatial characteristics of the gas compartment. The influences of a few parameters, such as initial conditions and section size of the gas compartment, on the shock wave propagation rule are further discussed. The basic procedure for predicting the peak pressure of the blast wave is provided by considering the initial conditions and the gas compartment, and the corresponding injury effect of the explosion wave on the living beings is assessed. The investigation demonstrates that the peak pressure by the coupled effect between the initial conditions is significantly influenced, especially at the upper and lower gas explosion limits. The peak pressure increases gradually as the width or height increases, and both basically meet the linear relation. The proposed method can forecast the peak pressure of the explosion shock wave in the gas compartment accurately. According to the peak pressure longitudinal and transversal distributions of the blast wave, the peak pressure is far greater than the killing pressure threshold in the underground and closed space; consequently, it is not safe for the living beings in the gas compartment.

Lin, Shu-Chao↗

DOE OSTI2022

Protective Effect of Phloretin against Hydrogen Peroxide-Induced Oxidative Damage by Enhancing Autophagic Flux in DF-1 Cells

Phloretin (PHL) is a dihydrochalcone flavonoid isolated from the peel and root bark of apples, strawberries, and other plants with antioxidative characteristic. In this study, we aimed to investigate the protective effect and the potential mechanism of PHL on hydrogen peroxide (H2O2)-induced oxidative damage in DF-1 cells. The results showed that PHL exhibited no cytotoxic effect on DF-1 cells at concentration below 20 μM. PHL markedly increased H2O2-reduced cell viability, decreased H2O2-induced apoptosis, as evidenced by reduced apoptosis rate, the upregulation of gene and protein level of Bcl-2, and the downregulation of gene and protein level of Bax and Cleaved caspase3. In addition, PHL reduced H2O2-induced reactive oxygen species (ROS) production and restored antioxidant enzymes activities as well as mitochondrial membrane potential in a dose-dependent manner. Moreover, PHL prior to H2O2 further increased LC3-II level, promoted p62 turnover and improved lysosomal function. Importantly, autophagy inhibitor chloroquine (CQ) reversed the protective effect of PHL, and increased H2O2-induced apoptosis. Furthermore, PHL inhibited the phosphorylation levels of ERK, p38, and JNK. Collectively, these results indicate that PHL could attenuate H2O2-induced oxidative injury and apoptosis by maintaining lysosomal function and promoting autophagic flux, and MAPKs pathway may be involved in this process. Our study provides evidence that PHL could as a new strategy to against oxidative damage in poultry industry.

Song, Dan↗

DOE OSTI2020

Exosomes From Induced Pluripotent Stem Cell–Derived Cardiomyocytes Promote Autophagy for Myocardial Repair

Background. Induced pluripotent stem cells and their differentiated cardiomyocytes (iCMs) have tremendous potential as patient-specific therapy for ischemic cardiomyopathy following myocardial infarctions, but difficulties in viable transplantation limit clinical translation. Exosomes secreted from iCMs (iCM-Ex) can be robustly collected in vitro and injected in lieu of live iCMs as a cell-free therapy for myocardial infarction. Methods and Results. iCM-Ex were precipitated from iCM supernatant and characterized by protein marker expression, nanoparticle tracking analysis, and functionalized nanogold transmission electron microscopy. iCM-Ex were then used in in vitro and in vivo models of ischemic injuries. Cardiac function in vivo was evaluated by left ventricular ejection fraction and myocardial viability measurements by magnetic resonance imaging. Cardioprotective mechanisms were studied by JC-1 (tetraethylbenzimidazolylcarbocyanine iodide) assay, immunohistochemistry, quantitative real-time polymerase chain reaction, transmission electron microscopy, and immunoblotting. iCM-Ex measured ≈140 nm and expressed CD63 and CD9. iCM and iCM-Ex microRNA profiles had significant overlap, indicating that exosomal content was reflective of the parent cell. Mice treated with iCM-Ex demonstrated significant cardiac improvement post–myocardial infarction, with significantly reduced apoptosis and fibrosis. In vitro iCM apoptosis was significantly reduced by hypoxia and exosome biogenesis inhibition and restored by treatment with iCM-Ex or rapamycin. Autophagosome production and autophagy flux was upregulated in iCM-Ex groups in vivo and in vitro. Conclusions. iCM-Ex improve post–myocardial infarction cardiac function by regulating autophagy in hypoxic cardiomyoytes, enabling a cell-free, patient-specific therapy for ischemic cardiomyopathy.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2023

T cell activation is insufficient to drive SIV disease progression

Resolution of T cell activation and inflammation is a key determinant of the lack of SIV disease progression in African green monkeys (AGMs). Although frequently considered together, T cell activation occurs in response to viral stimulation of acquired immunity, while inflammation reflects innate immune responses to mucosal injury. We dissociated T cell activation from inflammation through regulatory T cell (Treg) depletion with Ontak (interleukin-2 coupled with diphtheria toxin) during early SIV infection of AGMs. This intervention abolished control of T cell immune activation beyond the transition from acute to chronic infection. Ontak had no effect on gut barrier integrity, microbial translocation, inflammation, and hypercoagulation, despite increasing T cell activation. Ontak administration increased macrophage counts yet decreased their activation. Persistent T cell activation influenced SIV pathogenesis, shifting the ramp-up in viral replication to earlier time points, prolonging the high levels of replication, and delaying CD4 + T cell restoration yet without any clinical or biological sign of disease progression in Treg-depleted AGMs. Thus, by inducing T cell activation without damaging mucosal barrier integrity, we showed that systemic T cell activation per se is not sufficient to drive disease progression, which suggests that control of systemic inflammation (likely through maintenance of gut integrity) is the key determinant of lack of disease progression in natural hosts of SIVs.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2024

Proteomics identifies complement protein signatures in patients with alcohol-associated hepatitis

Diagnostic challenges continue to impede development of effective therapies for successful management of alcohol-associated hepatitis (AH), creating an unmet need to identify noninvasive biomarkers for AH. In murine models, complement contributes to ethanol-induced liver injury. Therefore, we hypothesized that complement proteins could be rational diagnostic/prognostic biomarkers in AH. Here, we performed a comparative analysis of data derived from human hepatic and serum proteome to identify and characterize complement protein signatures in severe AH (sAH). The quantity of multiple complement proteins was perturbed in liver and serum proteome of patients with sAH. Multiple complement proteins differentiated patients with sAH from those with alcohol cirrhosis (AC) or alcohol use disorder (AUD) and healthy controls (HCs). Serum collectin 11 and C1q binding protein were strongly associated with sAH and exhibited good discriminatory performance among patients with sAH, AC, or AUD and HCs. Furthermore, complement component receptor 1-like protein was negatively associated with pro-inflammatory cytokines. Additionally, lower serum MBL associated serine protease 1 and coagulation factor II independently predicted 90-day mortality. In summary, meta-analysis of proteomic profiles from liver and circulation revealed complement protein signatures of sAH, highlighting a complex perturbation of complement and identifying potential diagnostic and prognostic biomarkers for patients with sAH.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2024

An Accurate and Automated Convective Vortex Detection Method for Long-Duration Infrasound Microbarometer Data

Heating of the surficial layer of the atmosphere often generates convective vortices, known as “dust devils” when they entrain visible debris. Convective vortices are common on both Earth and Mars, where they affect the climate via dust loading, contribute to wind erosion, impact the efficiency of photovoltaic systems, and potentially result in injury and property damage. However, long-duration terrestrial convective vortex activity records are rare. We have developed a high-precision and high-recall method to extract convective vortex signatures from infrasound microbarometer data streams. The techniques utilizes a wavelet-based detector to capture potential events and then a template matching system to extract the duration of the vortex. Since permanent and temporary infrasound sensors networks are present throughout the globe (many with open data), our method unlocks a vast new convective vortex dataset without requiring the deployment of specialized instrumentation.

54 ENVIRONMENTAL SCIENCES↗

DOE OSTI2021

Global transcriptome profile of the developmental principles of in vitro iPSC-to-motor neuron differentiation

Abstract Background Human induced pluripotent stem cells (iPSC) have opened new avenues for regenerative medicine. Consequently, iPSC-derived motor neurons have emerged as potentially viable therapies for spinal cord injuries and neurodegenerative disorders including Amyotrophic Lateral Sclerosis. However, direct clinical application of iPSC bears in itself the risk of tumorigenesis and other unforeseeable genetic or epigenetic abnormalities. Results Employing RNA-seq technology, we identified and characterized gene regulatory networks triggered by in vitro chemical reprogramming of iPSC into cells with the molecular features of motor neurons (MNs) whose function in vivo is to innervate effector organs. We present meta-transcriptome signatures of 5 cell types: iPSCs, neural stem cells, motor neuron progenitors, early motor neurons, and mature motor neurons. In strict response to the chemical stimuli, along the MN differentiation axis we observed temporal downregulation of tumor growth factor-β signaling pathway and consistent activation of sonic hedgehog, Wnt/β-catenin, and Notch signaling. Together with gene networks defining neuronal differentiation (neurogenin 2, microtubule-associated protein 2, Pax6, and neuropilin-1), we observed steady accumulation of motor neuron-specific regulatory genes, including Islet-1 and homeobox protein HB9. Interestingly, transcriptome profiling of the differentiation process showed that Ca 2+ signaling through cAMP and LPC was downregulated during the conversion of the iPSC to neural stem cells and key regulatory gene activity of the pathway remained inhibited until later stages of motor neuron formation. Pathways shaping the neuronal development and function were well-represented in the early motor neuron cells including, neuroactive ligand-receptor interactions, axon guidance, and the cholinergic synapse formation. A notable hallmark of our in vitro motor neuron maturation in monoculture was the activation of genes encoding G-coupled muscarinic acetylcholine receptors and downregulation of the ionotropic nicotinic acetylcholine receptors expression. We observed the formation of functional neuronal networks as spontaneous oscillations in the extracellular action potentials recorded on multi-electrode array chip after 20 days of differentiation. Conclusions Detailed transcriptome profile of each developmental step from iPSC to motor neuron driven by chemical induction provides the guidelines to novel therapeutic approaches in the re-construction efforts of muscle innervation.

59 BASIC BIOLOGICAL SCIENCES↗