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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 577 records · Page 32
All sourcesNASA NTRSDOE OSTI
DOE OSTI2014

The novel steroidal alkaloids dendrogenin A and B promote proliferation of adult neural stem cells

Highlights: • Dendrogenin A and B are new aminoalkyl oxysterols. • Dendrogenins stimulated neural stem cells proliferation. • Dendrogenins induce neuronal outgrowth from neurospheres. • Dendrogenins provide new therapeutic options for neurodegenerative disorders. - Abstract: Dendrogenin A (DDA) and dendrogenin B (DDB) are new aminoalkyl oxysterols which display re-differentiation of tumor cells of neuronal origin at nanomolar concentrations. We analyzed the influence of dendrogenins on adult mice neural stem cell proliferation, sphere formation and differentiation. DDA and DDB were found to have potent proliferative effects in neural stem cells. Additionally, they induce neuronal outgrowth from neurospheres during in vitro cultivation. Taken together, our results demonstrate a novel role for dendrogenins A and B in neural stem cell proliferation and differentiation which further increases their likely importance to compensate for neuronal cell loss in the brain.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Selenomethionine promoted hippocampal neurogenesis via the PI3K-Akt-GSK3β-Wnt pathway in a mouse model of Alzheimer's disease

The maintenance of neural system integrity and function is the ultimate goal for the treatment of neurodegenerative disease such as Alzheimer's disease (AD). Neurogenesis plays an integral role in the maintenance of neural and cognitive functions, and its dysfunction is regarded as a major cause of cognitive impairment in AD. Moreover, the induction of neurogenesis by targeting endogenous neural stem cells (NSCs) is considered as one of the most promising treatment strategies. Our previous studies demonstrated that selenomethionine (Se-Met) was able to reduce β-amyloid peptide (Aβ) deposition, decrease Tau protein hyperphosphorylation and markedly improve cognitive functions in triple transgenic (3xTg) AD mice. In this study, we reported that the therapeutic effect of Se-Met on AD could also be due to neurogenesis modulation. By using the cultured hippocampal NSCs from 3xTg AD mice, we discovered that Se-Met (1–10 μM) with low concentration could promote NSC proliferation, while the one with a high concentration (50,100 μM) inhibiting proliferation. In subsequent studies, we also found that Se-Met activated the signaling pathway of PI3K/Akt, and thereby inhibited the GSK3β activity, which would further activated the β-catenin/Cyclin-D signaling pathway and promote NSC proliferation. Besides, after the induction of Se-Met, the number of neurons differentiated from NSCs significantly increased, and the number of astrocytes decreased. After a 90-day treatment with Se-Met (6 μg/mL), the number of hippocampal neurons in 4-month-old AD mice increased significantly, while the one of astrocyte saw a sharp drop. Thus, Se-Met treatment promoted NSCs differentiation into neurons, and subsequently repaired damaged neural systems in AD mice. Being consistent with our in vitro studies, Se-Met acts through the PI3K-Akt- GSK3β-Wnt signaling pathway in vivo. This study provides an unparalleled evidence that selenium (Se) compounds are, to some extent, effective in promoting neurogenesis, and therefore we propose a novel mechanism for Se-Met treatment in AD. - Highlights: • It's the first time to evidence that a selenium (Se) compounds is effective in promoting neurogenesis. • Selenomethionine promotes neural stem cell proliferation and differentiation into neurons. • Selenomethionine activates the PI3K-Akt-GSK3β signaling pathway. • Selenomethionine activates the Wnt signaling pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

miR-137 attenuates Aβ-induced neurotoxicity through inactivation of NF-κB pathway by targeting TNFAIP1 in Neuro2a cells

Background: Accumulation of β-amyloid (Aβ) and neuroinflammation are implicated in the pathogenesis and development of Alzheimer's disease (AD). Neuron-enriched miR-137 was aberrantly downregulated and may be associated with the pathogenesis of AD. However, the detailed function of miR-137 in AD pathogenesis and the molecular mechanism have not been elucidated. Methods: The expressions of miR-137 and tumor necrosis factor alpha (TNFα)-induced protein 1 (TNFAIP1) at mRNA and protein levels in primary mouse cortical neurons and Neuro2a (N2a) cells exposed to different concentrations of Aβ{sub 25-35} were examined by qRT-PCR and western blot. Luciferase reporter assay was used to confirm the potential target of miR-137. MTT assay, flow cytometry analysis, caspase-3 activity assay, Enzyme-linked immunosorbent assay (ELISA), and western blot were used to detect cell viability, apoptosis, caspase-3 activity, Nuclear factor-kappa B (NF-κB) activity and level, respectively. Results: Aβ{sub 25-35} downregulated miR-137 and upregulated TNFAIP1 in primary mouse cortical neurons and N2a cells. In addition, miR-137 was found to directly target TNFAIP1 and suppress its mRNA and protein levels. Moreover, miR-137 restoration and TNFAIP1 knockdown facilitate Aβ{sub 25-35}-induced cell toxicity, apoptosis, caspase-3 activity, and activated NF-κB in N2a cells, which was partially abolished by TNFAIP1 overexpression. Conclusion: miR-137 attenuated Aβ-induced neurotoxicity through inactivation of NF-κB pathway by targeting TNFAIP1 in N2a cells, shedding light on the molecular mechanism of miR-137 underlying Aβ-induced neurotoxicity. - Highlights: • Aβ{sub 25-35} downregulated miR-137 and upregulated TNFAIP1 in cortical neurons and N2a cells. • miR-137 suppressed TNFAIP1 expression through direct binding at the 3′UTR. • miR-137 overexpression contributed to Aβ{sub 25-35}-induced cell toxicity and apoptosis. • miR-137 overexpression on Aβ{sub 25-35}-induced neurotoxicity activated NF-κB pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

GAS5 silencing protects against hypoxia/ischemia-induced neonatal brain injury

Highlights: • GAS5 expression is increased after neonatal hypoxic/ischemic brain injury. • GAS5 knockdown protects hippocampal cells against hypoxic/ischemic stress. • GAS5 regulates hippocampal neuron function by sponging miR-23a. • GAS5 knockdown alleviates hypoxic/ischemic brain injury in vivo. Hypoxic/ischemic brain damage (HIBD) leads to high neonatal mortality and severe neurologic morbidity. However, the molecular mechanism of HIBD in the neonatal infant is still elusive. Long non-coding RNAs are shown as important regulators of brain development and many neurological diseases. Here, we determined the role of long noncoding RNA-GAS5 in HIBD. GAS5 expression was significantly up-regulated in hypoxic/ischemic-injured neonatal brain and hippocampal neurons. GAS5 silencing protected against hypoxic/ischemic-induced brain injury in vivo and primary hippocampal neuron injury in vitro. Mechanistically, GAS5 regulated hippocampal neuron function by sponging miR-23a. Intracerebroventricular injection of GAS5 shRNA significantly decreased brain GAS5 expression, reduced brain infarct size, and improved neurological function recovery. Collectively, this study suggests a promising therapeutic approach of GAS5 inhibition in the treatment of neonatal HIBD.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Crybb2 associates with Tmsb4X and is crucial for dendrite morphogenesis

Highlights: • A structural protein of ocular lens, Crybb2, has function in neuronal development. • Crybb2 contributes to dendritogenesis in vitro and in vivo. • Tmsb4X up-regulated in Crybb2 mutants mouse brain. • Overexpression of Tmsb4X inhibits dendritogenesis phenocopied the Crybb2 knock-down in hippocampal neuron. Dendrite morphogenesis is a complex but well-orchestrated process. Various studies reported the involvement of alteration in dendrite morphology in different brain disorders, including neuropsychiatric disorders. Initially, βB2-crystallin (gene symbol: Crybb2/CRYBB2) has been described as a structural protein of the ocular lens. Mutations of the corresponding gene, Crybb2, lead to cataract. Recent studies in mice suggested that mutations in Crybb2 cause alterations in hippocampal morphology and function, albeit its function in hippocampal neuron development remained elusive. In the current study, we found that Crybb2 contributes to dendritogenesis in vitro and in vivo. Furthermore, screening of previous data on differential expression-arrays, we found Tmsb4X up-regulated in Crybb2 mutants mouse brain. Additionally, Tmsb4X was co-expressed with Crybb2 at actin-enriched cell ruffles. Over-expression of Tmsb4X in cultured hippocampal neurons inhibited dendritogenesis, which phenocopied Crybb2 knock-down. The current study uncovers a new function of Crybb2 in brain development, especially in dendritogenesis, and the possible interplay partner Tmsb4X involved in this process.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Pull down assay for GTP-bound form of Sar1a reveals its activation during morphological differentiation

Highlights: • The C-terminal region of Sec23B is available for a Sar1a pull down assay. • Neuronal differentiation correlates to an increase in GTP-bound Sar1a. • Oligodendrocyte differentiation correlates to an increase in GTP-bound Sar1a. • PREB binding to nucleotide-free Sar1a also increases during differentiation. The intracellular molecular transport system is a basic and general cellular mechanism that is regulated by an array of signaling molecules. Sar1 small GTPases are molecules that play a key role in controlling vehicle transport between the endoplasmic reticulum (ER) and Golgi bodies. Like other small GTPases, the activities of Sar1a depend on their guanine-nucleotide-binding states, which are regulated by guanine-nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Despite the well-known function of mammalian Sar1 in the intracellular transport system, little is known about when and how Sar1 is activated during cell morphological changes. Here we show that the C-terminal, but not the N-terminal, regions of Sec23A and Sec23B, the effector proteins of Sar1a, specifically bind to the active, GTP-bound form of Sar1a. An affinity precipitation (pull-down) assay using a recombinant C-terminal region of Sec23B reveals that Sar1a is activated following differentiation in neuronal cell lines. In neuronal N1E-115 cells, GTP-bound Sar1a is increased when cells elongate neuronal processes. Similar results are observed in morphological differentiation in oligodendroglial FBD-102b cells. Additionally, prolactin regulatory element binding (PREB), the GEF for Sar1 (Sar1 activator), increases the binding ability to the nucleotide-free form of Sar1a when morphological differentiation occurs. Nucleotide-free small GTPases preferentially interact with the cognate, active GEFs. These results provide evidence that using previously unreported pull down assays reveals that Sar1 and PREB are upregulated following the induction of morphological differentiation, suggesting the potential role of signaling through Sar1a during morphological differentiation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Resistin destroys mitochondrial biogenesis by inhibiting the PGC-1α/ NRF1/TFAM signaling pathway

Highlights: • Resistin caused impairment of mitochondrial biogenesis in neuronal cells. • Resistin induced loss of mitochondrial function by reducing respiration rate and ATP. • Resistin inhibited the PGC-1α/NRF1/TFAM pathway. • PGC-1α abolished the inhibitory effects of resistin in mitochondrial biogenesis. Mitochondrial biogenesis deficits in neuronal cells are associated with the pathological progression of neurodegenerative diseases. Resistin, a secretory adipocytokine, possesses multiple physiological functions in diverse cells and tissues. However, the effects of resistin on mitochondrial biogenesis in neuronal cells are still elusive. In the current study, we found that resistin caused a sustainable decrease in mitochondrial contents, including mitochondrial DNA/nuclear DNA ratio (mtDNA/nDNA), mitochondrial mass, cytochrome b protein expression, and cytochrome c oxidase activity, which were correlated with “loss of mitochondrial function” including reduced mitochondrial respiration rate and ATP production in human SH-SY5Y neuronal cells. Indeed, resistin treatment destroyed the expression of peroxisome proliferator activator receptor gamma-coactivator 1α (PGC-1α), a master regulator of mitochondrial biogenesis, as well as its downstream target genes including nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM). Notably, overexpression of PGC-1α could completely rescue mitochondrial biogenesis and mitochondrial deficits induced by resistin. Mechanistically, inhibition of 5′-adenosine monophosphate-activated protein kinase (AMPK) was shown to mediate the inhibitory effects of resistin on mitochondrial biogenesis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Clozapine increased c-Fos protein expression in several brain subregions of socially isolated rats

Chronic social stress and/or pharmacological treatments differentially modulate the expression of c-Fos, a marker of neuronal activity, in subregions of the rat brain. Here, we examined the effect of the atypical antipsychotic Clozapine (Clz) (20 mg/kg/day for 3 weeks) on the neuronal activation pattern of c-Fos protein expression in stress-relevant brain subregions of adult male Wistar rats exposed to chronic social isolation (CSIS: 3 weeks), an animal model of depression and schizophrenia, and controls. The protein expression of c-Fos was also used to map neuronal populations in brain subregions activated by CSIS alone. Subregions which showed significantly increased c-Fos protein expression following CSIS included the retrosplenial cortex (RSC), (subregions:RSC granular cortex, c region (RSGc) and dysgranular (RSD)), dentate gyrus, dorsal (DGd), paraventricular thalamic nucleus, posterior part (PVP), lateral (LA)/basolateral (BL) complex of amygdala, caudate putamen (CPu) and accumbens nucleus, shell (AcbSh). Increases in c-Fos protein expression in the RSGc, RSD, DGd, PVP, LA/BL complex of amygdala and striatum (CPu, Acb Core (AcbC) and AcbSh) following Clz treatment in controls were found. Clz applied simultaneously with CSIS modulated neuronal activity in CPu, AcbC and AcbSh subregions compared to CSIS alone, increasing c-Fos protein expression. Furthermore, Clz revealed synergistic effects with CSIS in the CA1d and PVP. These identified neural circuits reflect brain subregions activated following CSIS and/or Clz administration. These data further contribute to the understanding of the effectiveness of Clz in the modulation of brain subregion activation in response to CSIS. © 2019.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Effects of Aging on Hippocampal Neurogenesis After Irradiation

Purpose: To assess the influence of aging on hippocampal neuronal development after irradiation (IR). Methods and Materials: Male mice, 2, 4, 6, 12, and 18 months of age, were given a single dose of 0 or 5 Gy of IR. A bromodeoxyuridine (BrdU) incorporation study was used to label newborn cells. Neural progenitors, newborn neurons, and microglia in dentate gyrus (DG) were identified by phenotypic markers, and their numbers were quantified by nonbiased stereology 9 weeks after IR. Results: BrdU-positive or newborn cells in DG decreased with aging and after IR. The number of neuroblasts and newborn neurons decreased with aging, and a further significant reduction was observed after IR. Total type 1 cells (the putative neural stem cells), and newborn type 1 cells decreased with aging, and further reduction in total type 1 cells was observed after IR. Aging-associated activation of microglia in hippocampus was enhanced after IR. Conclusions: The aging-associated decline in hippocampal neurogenesis was further inhibited after IR. Ablation of neural progenitors and activation of microglia may contribute to the inhibition of neuronal development after IR across all ages.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2017

Later Life Changes in Hippocampal Neurogenesis and Behavioral Functions After Low-Dose Prenatal Irradiation at Early Organogenesis Stage

Purpose: To investigate long-term changes in behavioral functions of mice after exposure to low-dose prenatal radiation at an early organogenesis stage. Methods and Materials: Pregnant C57BL/6J mice were irradiated (20 cGy) at postcoitus day 5.5. The male and female offspring were subjected to different behavioral assays for affective, motor, and cognitive functions at 3, 6, and 12 months of age. Behavioral functions were further correlated with the population of CA1 and CA3 pyramidal neurons and immature neurons in hippocampal dentate gyrus. Results: Prenatally exposed mice of different age groups showed a sex-specific pattern of sustained changes in behavioral functions. Male mice showed significant changes in anxiety-like phenotypes, learning, and long-term memory at age 3 months. At 6 months of age such behavioral functions were recovered to a normal level but could not be sustained at age 12 months. Female mice showed an appreciable recovery in almost all behavioral functions at 12 months. Patterns of change in learning and long-term memory were comparable to the population of CA1 and CA3 pyramidal neurons and doublecortin-positive neurons in hippocampus. Conclusion: Our finding suggests that prenatal (early organogenesis stage) irradiation even at a lower dose level (20 cGy) is sufficient to cause potential changes in neurobehavioral function at later stages of life. Male mice showed relatively higher vulnerability to radiation-induced neurobehavioral changes as compared with female.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2023

Protein–protein interactions between tenascin-R and RPTPζ/phosphacan are critical to maintain the architecture of perineuronal nets

Neural plasticity, the ability to alter the structure and function of neural circuits, varies throughout the age of an individual. The end of the hyperplastic period in the central nervous system coincides with the appearance of honeycomb-like structures called perineuronal nets (PNNs) that surround a subset of neurons. PNNs are a condensed form of neural extracellular matrix that include the glycosaminoglycan hyaluronan and extracellular matrix proteins such as aggrecan and tenascin-R (TNR). PNNs are key regulators of developmental neural plasticity and cognitive functions, yet our current understanding of the molecular interactions that help assemble them remains limited. Disruption of Ptprz1, the gene encoding the receptor protein tyrosine phosphatase RPTPζ, altered the appearance of nets from a reticulated structure to puncta on the surface of cortical neuron bodies in adult mice. The structural alterations mirror those found in Tnr -/- mice, and TNR is absent from the net structures that form in dissociated cultures of Ptprz1 -/- cortical neurons. These findings raised the possibility that TNR and RPTPζ cooperate to promote the assembly of PNNs. Here, we show that TNR associates with the RPTPζ ectodomain and provide a structural basis for these interactions. Furthermore, we show that RPTPζ forms an identical complex with tenascin-C, a homolog of TNR that also regulates neural plasticity. Finally, we demonstrate that mutating residues at the RPTPζ–TNR interface impairs the formation of PNNs in dissociated neuronal cultures. Overall, this work sets the stage for analyzing the roles of protein–protein interactions that underpin the formation of nets.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2022

Characterizing vertical upper ocean temperature structures in the European Arctic through unsupervised machine learning

In-situ observations of subsurface ocean temperatures are, in many regions, inconsistently distributed in time and space. These spatio-temporal inconsistencies in the observational network lead to difficulties in utilizing those observations effectively for ocean model evaluation or understanding larger-scale ocean characteristics. Model accuracy of subsurface ocean characteristics is especially important within regions that contain complex ocean structures. One such region is the European Arctic which not only contains several types of water masses with unique characteristics, but also wintertime sea ice coverage and complex bathymetry. This study presents an unsupervised neural networking technique that can be used in combination with traditional ocean model evaluation techniques to provide additional information on the accuracy of modeled vertical ocean temperature profiles. Self-organizing maps is an unsupervised machine learning technique that we apply to approximately twenty thousand Argo and CTD temperature profiles from 2012 to 2020 in the European Arctic to categorize the observed vertical ocean temperature structures in the top 150 m. The observed ocean profile categories, or neurons, defined by the self-organizing map show strong spatial and temporal dependencies. We then use the neuron weights, or the learned temperature profile structure of each neuron, to validate the spatial and temporal variability of modeled vertical temperature structures. This analysis gives us new insights about the model’s capabilities to reproduce specific vertical structures of the top-most ocean layer within different regions and seasons. Mapping modeled ocean temperature profiles onto the neuron-space of the observationally-defined self organized map highlights the potential of this method to advance our understanding of model deficiencies in that region.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2014

Ototoxicity of paclitaxel in rat cochlear organotypic cultures

Paclitaxel (taxol) is a widely used antineoplastic drug employed alone or in combination to treat many forms of cancer. Paclitaxel blocks microtubule depolymerization thereby stabilizing microtubules and suppressing cell proliferation and other cellular processes. Previous reports indicate that paclitaxel can cause mild to moderate sensorineural hearing loss and some histopathologic changes in the mouse cochlea; however, damage to the neurons and the underlying cell death mechanisms are poorly understood. To evaluate the ototoxicity of paclitaxel in more detail, cochlear organotypic cultures from postnatal day 3 rats were treated with paclitaxel for 24 or 48 h with doses ranging from 1 to 30 μM. No obvious histopathologies were observed after 24 h treatment with any of the paclitaxel doses employed, but with 48 h treatment, paclitaxel damaged cochlear hair cells in a dose-dependent manner and also damaged auditory nerve fibers and spiral ganglion neurons (SGN) near the base of the cochlea. TUNEL labeling was negative in the organ of Corti, but positive in SGN with karyorrhexis 48 h after 30 μM paclitaxel treatment. In addition, caspase-6, caspase-8 and caspase-9 labeling was present in SGN treated with 30 μM paclitaxel for 48 h. These results suggest that caspase-dependent apoptotic pathways are involved in paclitaxel-induced damage of SGN, but not hair cells in cochlea. - Highlights: • Paclitaxel was toxic to cochlear hair cells and spiral ganglion neurons. • Paclitaxel-induced spiral ganglion degeneration was apoptotic. • Paclitaxel activated caspase-6, -8 and -8 in spiral ganglion neurons.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Bronchopulmonary C-fibers' IL1RI contributes to the prolonged apneic response to intra-atrial injection of capsaicin by prenatal nicotinic exposure in rat pups

Prenatal nicotinic exposure (PNE) as a SIDS model reportedly sensitizes bronchopulmonary C-fibers (PCFs), contributing to the prolonged PCF-mediated apnea in rat pups, but the relevant mechanisms are not fully understood. Pulmonary IL-1β upregulated by cigarette smoke is known to stimulate or sensitize PCFs acting via IL-1 type I receptor (IL1RI) and inhibit inspiration frequency. Because of its upregulation observed in SIDS victims, we hypothesized that PNE increased pulmonary IL-1β release and IL1RI expression in pulmonary C-neurons via action on α7 nicotinic acetylcholine receptors (α7nAChR) to induce the prolonged PCF-mediated apnea. IL-1β in BALF and IL1RI in the nodose/jugular (N/J) ganglion and vagal pulmonary C-neurons retrogradely-traced were compared between Ctrl (saline) and PNE pups and among the vehicle-treated Ctrl and PNE and methyllycaconitine (a selective α7nAChR antagonist)-treated PNE pups. The effect of IL-1RI blockade (IL-1Ra) on the PCF-mediated apnea was also compared between Ctrl and PNE pups. PNE significantly elevated IL-1β in BALF and upregulated IL1RI gene and protein expression in N/J ganglia and gene in vagal pulmonary C-neurons. All of these responses were eliminated by pretreatment with blockade of α7nAChR. In addition, the prolonged PCF-mediated apnea in PNE pups was significantly shortened by right atrial bolus injection of IL-1Ra. We conclude that PNE enhances pulmonary IL-1β release and PCF IL1RI expression acting via α7nAChR in contributing to sensitization of PCFs and prolongation of the PCF-mediated apneic response. - Highlights: • PNE increased pulmonary IL-1β release and IL1R1 expression in the N/J ganglia. • PNE elevated IL1R1 mRNA in vagal pulmonary C-neurons. • Blockage of peripheral IL1R1 reduced the PNE-induced PCF sensitization. • PNE induced the changes in IL-1β and IL1R1 dependent on action of α7nAChR.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Effects of oxidative stress on hyperglycaemia-induced brain malformations in a diabetes mouse model

Pregestational diabetes mellitus (PGDM) enhances the risk of fetal neurodevelopmental defects. However, the mechanism of hyperglycaemia-induced neurodevelopmental defects is not fully understood. In this study, several typical neurodevelopmental defects were identified in the streptozotocin-induced diabetes mouse model. The neuron-specific class III beta-tubulin/forkhead box P1-labelled neuronal differentiation was suppressed and glial fibrillary acidic protein-labelled glial cell lineage differentiation was slightly promoted in pregestational diabetes mellitus (PGDM) mice. Various concentrations of glucose did not change the U87 cell viability, but glial cell line-derived neurotrophic factor expression was altered with varying glucose concentrations. Mouse maternal hyperglycaemia significantly increased Tunel{sup +} apoptosis but did not dramatically affect PCNA{sup +} cell proliferation in the process. To determine the cause of increased apoptosis, we determined the SOD activity, the expression of Nrf2 as well as its downstream anti-oxidative factors NQO1 and HO1, and found that all of them significantly increased in PGDM fetal brains compared with controls. However, Nrf2 expression in U87 cells was not significantly changed by different glucose concentrations. In mouse telencephalon, we observed the co-localization of Tuj-1 and Nrf2 expression in neurons, and down-regulating of Nrf2 in SH-SY5Y cells altered the viability of SH-SY5Y cells exposed to high glucose concentrations. Taken together, the data suggest that Nrf2-modulated antioxidant stress plays a crucial role in maternal hyperglycaemia-induced neurodevelopmental defects. - Highlights: • Typical neurodevelopmental defects could be observed in STZ-treated mouse fetuses. • Nrf2 played a crucial role in hyperglycaemia-induced brain malformations. • The effects of hyperglycaemia on neurons and glia cells were not same.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Myosin Id localizes in dendritic spines through the tail homology 1 domain

Highlights: • Myosin Id is a synapse-related molecule that binds to actin filaments. • Myosin Id localizes in dendritic spines of primary hippocampal neurons. • The tail homology 1 domain is critical for the localization of myosin Id. Dendritic spines, the postsynaptic compartments at excitatory synapses, are capable of changing their shape and size to modulate synaptic transmission. The actin cytoskeleton and a variety of actin-binding proteins play a critical role in the dynamics of dendritic spines. Class I myosins are monomeric motor proteins that move along actin filaments using the energy of ATP hydrolysis. Of these class I myosins, myosin Id, the mammalian homolog of Drosophila Myo31DF, has been reported to be expressed in neurons, whereas its subcellular localization in neurons remained unknown. Here, we investigated the subcellular localization of myosin Id and determined the domain responsible for it. We found that myosin Id is enriched in the F-actin-rich pseudopodia of HEK293T cells and in the dendritic spines of primary hippocampal neurons. Both deletion and substitution of the tail homology 1 (TH1) domain drastically diminishes its colocalization with F-actin. In addition, the mutant form lacking the TH1 domain is less distributed in dendritic spines than is the full-length form. Taken together, our findings reveal that myosin Id localizes in dendritic spines through the TH1 domain.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Effects of laminin-111 peptide coatings on rat neural stem/progenitor cell culture

Neurons require adhesive scaffolds for their growth and differentiation. Laminins are a major cell adhesive component of basement membranes and have various biological activities in the peripheral and central nervous systems. Here, we evaluated the biological activities of 5 peptides derived from laminin-111 as a scaffold for mouse neuroblastoma Neuro2a cells and rat neural stem/progenitor cells (NPCs). The 5 peptides showed Neuro2a cell attachment activity similar to that of poly-d-lysine. However, when NPCs were cultured on the peptides, 2 syndecan-binding peptides, AG73 (RKRLQVQLSIRT, mouse laminin α1 chain 2719-2730) and C16 (KAFDITYVRLKF, laminin γ1 chain 139–150), demonstrated significantly higher cell attachment and neurite extension activities than other peptides including integrin-binding ones. Long-term cell culture experiments showed that both AG73 and C16 supported the growth of neurons and astrocytes that had differentiated from NPCs. Furthermore, C16 markedly promoted the expression of neuronal markers such as synaptosomal-associated protein-25 and syntaxin 1A. These results indicate that AG73 and C16 are useful for NPC cultures and that C16 can be applied to specialized research on synapses in differentiated neurons. These peptides have the potential for use as valuable biomaterials for NPC research.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Three-dimensional alteration of neurites in schizophrenia

Psychiatric symptoms of schizophrenia suggest alteration of cerebral neurons. However, the physical basis of the schizophrenia symptoms has not been delineated at the cellular level. Here, we report nanometer-scale three-dimensional analysis of brain tissues of schizophrenia and control cases. Structures of cerebral tissues of the anterior cingulate cortex were visualized with synchrotron radiation nanotomography. Tissue constituents visualized in the three-dimensional images were traced to build Cartesian coordinate models of tissue constituents, such as neurons and blood vessels. The obtained Cartesian coordinates were used for calculating curvature and torsion of neurites in order to analyze their geometry. Results of the geometric analyses indicated that the curvature of neurites is significantly different between schizophrenia and control cases. The mean curvature of distal neurites of the schizophrenia cases was similar to 1.5 times higher than that of the controls. The schizophrenia case with the highest neurite curvature carried a frame shift mutation in the GLO1 gene, suggesting that oxidative stress due to the GLO1 mutation caused the structural alteration of the neurites. The differences in the neurite curvature result in differences in the spatial trajectory and hence alter neuronal circuits. It has been shown that the anterior cingulate cortex analyzed in this study has emotional and cognitive functions. We suggest that the structural alteration of neurons in the schizophrenia cases should reflect psychiatric symptoms of schizophrenia.

60 APPLIED LIFE SCIENCES↗