Magnetic stem cell targeting to the inner ear

NASA Astrophysics Data System (ADS)

Le, T. N.; Straatman, L.; Yanai, A.; Rahmanian, R.; Garnis, C.; Häfeli, U. O.; Poblete, T.; Westerberg, B. D.; Gregory-Evans, K.

2017-12-01

Severe sensorineural deafness is often accompanied by a loss of auditory neurons in addition to injury of the cochlear epithelium and hair cell loss. Cochlear implant function however depends on a healthy complement of neurons and their preservation is vital in achieving optimal results. We have developed a technique to target mesenchymal stem cells (MSCs) to a deafened rat cochlea. We then assessed the neuroprotective effect of systematically delivered MSCs on the survival and function of spiral ganglion neurons (SGNs). MSCs were labeled with superparamagnetic nanoparticles, injected via the systemic circulation, and targeted using a magnetized cochlea implant and external magnet. Neurotrophic factor concentrations, survival of SGNs, and auditory function were assessed at 1 week and 4 weeks after treatments and compared against multiple control groups. Significant numbers of magnetically targeted MSCs (>30 MSCs/section) were present in the cochlea with accompanied elevation of brain-derived neurotrophic factor and glial cell-derived neurotrophic factor levels (p < 0.001). In addition we saw improved survival of SGNs (approximately 80% survival at 4 weeks). Hearing threshold levels in magnetically targeted rats were found to be significantly better than those of control rats (p < 0.05). These results indicate that magnetic targeting of MSCs to the cochlea can be accomplished with a magnetized cochlear permalloy implant and an external magnet. The targeted stem cells release neurotrophic factors which results in improved SGN survival and hearing recovery. Combining magnetic cell-based therapy and cochlear implantation may improve cochlear implant function in treating deafness.

Identification of diverse nerve growth factor-regulated genes by serial analysis of gene expression (SAGE) profiling

PubMed Central

Angelastro, James M.; Klimaschewski, Lars; Tang, Song; Vitolo, Ottavio V.; Weissman, Tamily A.; Donlin, Laura T.; Shelanski, Michael L.; Greene, Lloyd A.

2000-01-01

Neurotrophic factors such as nerve growth factor (NGF) promote a wide variety of responses in neurons, including differentiation, survival, plasticity, and repair. Such actions often require changes in gene expression. To identify the regulated genes and thereby to more fully understand the NGF mechanism, we carried out serial analysis of gene expression (SAGE) profiling of transcripts derived from rat PC12 cells before and after NGF-promoted neuronal differentiation. Multiple criteria supported the reliability of the profile. Approximately 157,000 SAGE tags were analyzed, representing at least 21,000 unique transcripts. Of these, nearly 800 were regulated by 6-fold or more in response to NGF. Approximately 150 of the regulated transcripts have been matched to named genes, the majority of which were not previously known to be NGF-responsive. Functional categorization of the regulated genes provides insight into the complex, integrated mechanism by which NGF promotes its multiple actions. It is anticipated that as genomic sequence information accrues the data derived here will continue to provide information about neurotrophic factor mechanisms. PMID:10984536

Towards Clinical Application of Neurotrophic Factors to the Auditory Nerve; Assessment of Safety and Efficacy by a Systematic Review of Neurotrophic Treatments in Humans.

PubMed

Bezdjian, Aren; Kraaijenga, Véronique J C; Ramekers, Dyan; Versnel, Huib; Thomeer, Hans G X M; Klis, Sjaak F L; Grolman, Wilko

2016-11-26

Animal studies have evidenced protection of the auditory nerve by exogenous neurotrophic factors. In order to assess clinical applicability of neurotrophic treatment of the auditory nerve, the safety and efficacy of neurotrophic therapies in various human disorders were systematically reviewed. Outcomes of our literature search included disorder, neurotrophic factor, administration route, therapeutic outcome, and adverse event. From 2103 articles retrieved, 20 randomized controlled trials including 3974 patients were selected. Amyotrophic lateral sclerosis (53%) was the most frequently reported indication for neurotrophic therapy followed by diabetic polyneuropathy (28%). Ciliary neurotrophic factor (50%), nerve growth factor (24%) and insulin-like growth factor (21%) were most often used. Injection site reaction was a frequently occurring adverse event (61%) followed by asthenia (24%) and gastrointestinal disturbances (20%). Eighteen out of 20 trials deemed neurotrophic therapy to be safe, and six out of 17 studies concluded the neurotrophic therapy to be effective. Positive outcomes were generally small or contradicted by other studies. Most non-neurodegenerative diseases treated by targeted deliveries of neurotrophic factors were considered safe and effective. Hence, since local delivery to the cochlea is feasible, translation from animal studies to human trials in treating auditory nerve degeneration seems promising.

Biology of GDNF and its receptors - Relevance for disorders of the central nervous system.

PubMed

Ibáñez, Carlos F; Andressoo, Jaan-Olle

2017-01-01

A targeted effort to identify novel neurotrophic factors for midbrain dopaminergic neurons resulted in the isolation of GDNF (glial cell line-derived neurotrophic factor) from the supernatant of a rat glial cell line in 1993. Over two decades and 1200 papers later, the GDNF ligand family and their different receptor systems are now recognized as one of the major neurotrophic networks in the nervous system, important for the development, maintenance and function of a variety of neurons and glial cells. The many ways in which the four members of the GDNF ligand family can signal and function allow these factors to take part in the control of multiple types of processes, from neuronal survival to axon guidance and synapse formation in the developing nervous system, to synaptic function and regenerative responses in the adult. In this review, we will briefly summarize basic aspects of GDNF signaling mechanisms and receptor systems and then review our current knowledge of the physiology of GDNF activities in the central nervous system, with an eye to its relevance for neurodegenerative and neuropsychiatric diseases. Copyright © 2016 Elsevier Inc. All rights reserved.

Brain-derived neurotrophic factor levels under chronic natalizumab treatment in multiple sclerosis. A preliminary report.

PubMed

Văcăraş, Vitalie; Major, Zoltán Zsigmond; Buzoianu, Anca Dana

Our main purpose was to investigate if the chronic treatment with the disease-modifying drug natalizumab shows quantifiable effect on BDNF levels in multiple sclerosis patients. BDNF plasma concentration was evaluated using enzyme-linked immunosorbent assay in healthy individuals, not treated multiple sclerosis patients and patients treated with natalizumab. Multiple sclerosis patients have a significantly lower amount of peripheral BDNF than healthy individuals. Patients treated with natalizumab have significantly higher BDNF levels than not treated patients. Chronic natalizumab treatment is associated with significantly increased plasma BDNF concentration in multiple sclerosis. Copyright © 2017 Polish Neurological Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

I.V. infusion of brain-derived neurotrophic factor gene-modified human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat.

PubMed

Nomura, T; Honmou, O; Harada, K; Houkin, K; Hamada, H; Kocsis, J D

2005-01-01

I.V. delivery of mesenchymal stem cells prepared from adult bone marrow reduces infarction size and ameliorates functional deficits in rat cerebral ischemia models. Administration of the brain-derived neurotrophic factor to the infarction site has also been demonstrated to be neuroprotective. To test the hypothesis that brain-derived neurotrophic factor contributes to the therapeutic benefits of mesenchymal stem cell delivery, we compared the efficacy of systemic delivery of human mesenchymal stem cells and human mesenchymal stem cells transfected with a fiber-mutant F/RGD adenovirus vector with a brain-derived neurotrophic factor gene (brain-derived neurotrophic factor-human mesenchymal stem cells). A permanent middle cerebral artery occlusion was induced by intraluminal vascular occlusion with a microfilament. Human mesenchymal stem cells and brain-derived neurotrophic factor-human mesenchymal stem cells were i.v. injected into the rats 6 h after middle cerebral artery occlusion. Lesion size was assessed at 6 h, 1, 3 and 7 days using MR imaging, and histological methods. Functional outcome was assessed using the treadmill stress test. Both human mesenchymal stem cells and brain-derived neurotrophic factor-human mesenchymal stem cells reduced lesion volume and elicited functional improvement compared with the control sham group, but the effect was greater in the brain-derived neurotrophic factor-human mesenchymal stem cell group. ELISA analysis of the infarcted hemisphere revealed an increase in brain-derived neurotrophic factor in the human mesenchymal stem cell groups, but a greater increase in the brain-derived neurotrophic factor-human mesenchymal stem cell group. These data support the hypothesis that brain-derived neurotrophic factor contributes to neuroprotection in cerebral ischemia and cellular delivery of brain-derived neurotrophic factor can be achieved by i.v. delivery of human mesenchymal stem cells.

Association of BDNF Val66Met Polymorphism and Brain BDNF Levels with Major Depression and Suicide.

PubMed

Youssef, Mariam M; Underwood, Mark D; Huang, Yung-Yu; Hsiung, Shu-Chi; Liu, Yan; Simpson, Norman R; Bakalian, Mihran J; Rosoklija, Gorazd B; Dwork, Andrew J; Arango, Victoria; Mann, J John

2018-06-01

Brain-derived neurotrophic factor is implicated in the pathophysiology of major depressive disorder and suicide. Both are partly caused by early life adversity, which reduces brain-derived neurotrophic factor protein levels. This study examines the association of brain-derived neurotrophic factor Val66Met polymorphism and brain brain-derived neurotrophic factor levels with depression and suicide. We hypothesized that both major depressive disorder and early life adversity would be associated with the Met allele and lower brain brain-derived neurotrophic factor levels. Such an association would be consistent with low brain-derived neurotrophic factor mediating the effect of early life adversity on adulthood suicide and major depressive disorder. Brain-derived neurotrophic factor Val66Met polymorphism was genotyped in postmortem brains of 37 suicide decedents and 53 nonsuicides. Additionally, brain-derived neurotrophic factor protein levels were determined by Western blot in dorsolateral prefrontal cortex (Brodmann area 9), anterior cingulate cortex (Brodmann area 24), caudal brainstem, and rostral brainstem. The relationships between these measures and major depressive disorder, death by suicide, and reported early life adversity were examined. Subjects with the Met allele had an increased risk for depression. Depressed patients also have lower brain-derived neurotrophic factor levels in anterior cingulate cortex and caudal brainstem compared with nondepressed subjects. No effect of history of suicide death or early life adversity was observed with genotype, but lower brain-derived neurotrophic factor levels in the anterior cingulate cortex were found in subjects who had been exposed to early life adversity and/or died by suicide compared with nonsuicide decedents and no reported early life adversity. This study provides further evidence implicating low brain brain-derived neurotrophic factor and the brain-derived neurotrophic factor Met allele in major depression risk. Future studies should seek to determine how altered brain-derived neurotrophic factor expression contributes to depression and suicide.

Agomelatine Increases BDNF Serum Levels in Depressed Patients in Correlation with the Improvement of Depressive Symptoms

PubMed Central

Pettorruso, Mauro; De Berardis, Domenico; Varasano, Paola Annunziata; Lucidi Pressanti, Gabriella; De Remigis, Valeria; Valchera, Alessandro; Ricci, Valerio; Di Nicola, Marco; Janiri, Luigi; Biggio, Giovanni; Di Giannantonio, Massimo

2016-01-01

Background: Agomelatine modulates brain-derived neurotrophic factor expression via its interaction with melatonergic and serotonergic receptors and has shown promising results in terms of brain-derived neurotrophic factor increase in animal models. Methods: Twenty-seven patients were started on agomelatine (25mg/d). Venous blood was collected and brain-derived neurotrophic factor serum levels were measured at baseline and after 2 and 8 weeks along with a clinical assessment, including Hamilton Depression Rating Scale and Snaith-Hamilton Pleasure Scale. Results: Brain-derived neurotrophic factor serum concentration increased after agomelatine treatment. Responders showed a significant increase in brain-derived neurotrophic factor levels after 2 weeks of agomelatine treatment; no difference was observed in nonresponders. Linear regression analysis showed that more prominent brain-derived neurotrophic factor level variation was associated with lower baseline BDNF levels and greater anhedonic features at baseline. Conclusions: Patients affected by depressive disorders showed an increase of brain-derived neurotrophic factor serum concentration after a 2-week treatment with agomelatine. The increase of brain-derived neurotrophic factor levels was found to be greater in patients with lower brain-derived neurotrophic factor levels and marked anhedonia at baseline. PMID:26775293

Brain-derived neurotrophic factor transgenic mice exhibit passive avoidance deficits, increased seizure severity and in vitro hyperexcitability in the hippocampus and entorhinal cortex.

PubMed

Croll, S D; Suri, C; Compton, D L; Simmons, M V; Yancopoulos, G D; Lindsay, R M; Wiegand, S J; Rudge, J S; Scharfman, H E

1999-01-01

Transgenic mice overexpressing brain-derived neurotrophic factor from the beta-actin promoter were tested for behavioral, gross anatomical and physiological abnormalities. Brain-derived neurotrophic factor messenger RNA overexpression was widespread throughout brain. Overexpression declined with age, such that levels of overexpression decreased sharply by nine months. Brain-derived neurotrophic factor transgenic mice had no gross deformities or behavioral abnormalities. However, they showed a significant passive avoidance deficit. This deficit was dependent on continued overexpression, and resolved with age as brain-derived neurotrophic factor transcripts decreased. In addition, the brain-derived neurotrophic factor transgenic mice showed increased seizure severity in response to kainic acid. Hippocampal slices from brain-derived neurotrophic factor transgenic mice showed hyperexcitability in area CA3 and entorhinal cortex, but not in dentate gyrus. Finally, area CA1 long-term potentiation was disrupted, indicating abnormal plasticity. Our data suggest that overexpression of brain-derived neurotrophic factor in the brain can interfere with normal brain function by causing learning impairments and increased excitability. The results also support the hypothesis that excess brain-derived neurotrophic factor could be pro-convulsant in the limbic system.

A novel natural product inspired scaffold with robust neurotrophic, neurogenic and neuroprotective action

PubMed Central

Chakravarty, Sumana; Maitra, Swati; Reddy, R Gajendra; Das, Tapatee; Jhelum, Priya; Kootar, Scherazad; Rajan, Wenson D.; Samanta, Anumita; Samineni, Ramesh; Pabbaraja, Srihari; Kernie, Steven G.; Mehta, Goverdhan; Kumar, Arvind

2015-01-01

In search for drugs to treat neuropsychiatric disorders wherein neurotrophic and neurogenic properties are affected, two neurotrophically active small molecules specially crafted following natural product leads based on 2-oxa-spiro[5.5]-undecane scaffold, have been thoroughly evaluated for their neurotrophic, neurogenic and neuroprotective potential in ex vivo primary culture and in vivo zebrafish and mouse models. The outcome of in vivo investigations suggest that one of these molecules is more neurotrophic than neurogenic while the other one is more neurogenic than neurotrophic and the former exhibits remarkable neuroprotection in a mouse acute ischemic stroke model. The molecular mechanisms of action of these compounds appear to be through the TrkB-MEK-ERK-CREB-BDNF pathway as pre-treatment with neurotrophin receptor TrkB inhibitor ANA-12 and MEK inhibitor PD98059 attenuates the neurotrophic action of compounds. PMID:26388493

Synergistic Increase of Serum BDNF in Alzheimer Patients Treated with Cerebrolysin and Donepezil: Association with Cognitive Improvement in ApoE4 Cases

PubMed Central

Alvarez, Irene; Iglesias, Olalla; Crespo, Ignacio; Figueroa, Jesus; Aleixandre, Manuel; Linares, Carlos; Granizo, Elias; Garcia-Fantini, Manuel; Marey, Jose; Masliah, Eliezer; Winter, Stefan; Muresanu, Dafin; Moessler, Herbert

2016-01-01

Background: Low circulating brain derived neurotrophic factor may promote cognitive deterioration, but the effects of neurotrophic and combination drug therapies on serum brain derived neurotrophic factor were not previously investigated in Alzheimer’s disease. Methods: We evaluated the effects of Cerebrolysin, donepezil, and the combined therapy on brain derived neurotrophic factor serum levels at week 16 (end of Cerebrolysin treatment) and week 28 (endpoint) in mild-to-moderate Alzheimer’s disease patients. Results: Cerebrolysin, but not donepezil, increased serum brain derived neurotrophic factor at week 16, while the combination therapy enhanced it at both week 16 and study endpoint. Brain derived neurotrophic factor responses were significantly higher in the combination therapy group than in donepezil and Cerebrolysin groups at week 16 and week 28, respectively. Brain derived neurotrophic factor increases were greater in apolipoprotein E epsilon-4 allele carriers, and higher brain derived neurotrophic factor levels were associated with better cognitive improvements in apolipoprotein E epsilon-4 allele patients treated with Cerebrolysin and the combined therapy. Conclusion: Our results indicate a synergistic action of Cerebrolysin and donepezil to increase serum brain derived neurotrophic factor and delaying cognitive decline, particularly in Alzheimer’s disease cases with apolipoprotein E epsilon-4 allele. PMID:27207906

Neurotransmitter systems and neurotrophic factors in autism: association study of 37 genes suggests involvement of DDC.

PubMed

Toma, Claudio; Hervás, Amaia; Balmaña, Noemí; Salgado, Marta; Maristany, Marta; Vilella, Elisabet; Aguilera, Francisco; Orejuela, Carmen; Cuscó, Ivon; Gallastegui, Fátima; Pérez-Jurado, Luis Alberto; Caballero-Andaluz, Rafaela; Diego-Otero, Yolanda de; Guzmán-Alvarez, Guadalupe; Ramos-Quiroga, Josep Antoni; Ribasés, Marta; Bayés, Mònica; Cormand, Bru

2013-09-01

Neurotransmitter systems and neurotrophic factors can be considered strong candidates for autism spectrum disorder (ASD). The serotoninergic and dopaminergic systems are involved in neurotransmission, brain maturation and cortical organization, while neurotrophic factors (NTFs) participate in neurodevelopment, neuronal survival and synapses formation. We aimed to test the contribution of these candidate pathways to autism through a case-control association study of genes selected both for their role in central nervous system functions and for pathophysiological evidences. The study sample consisted of 326 unrelated autistic patients and 350 gender-matched controls from Spain. We genotyped 369 tagSNPs to perform a case-control association study of 37 candidate genes. A significant association was obtained between the DDC gene and autism in the single-marker analysis (rs6592961, P = 0.00047). Haplotype-based analysis pinpointed a four-marker combination in this gene associated with the disorder (rs2329340C-rs2044859T-rs6592961A-rs11761683T, P = 4.988e-05). No significant results were obtained for the remaining genes after applying multiple testing corrections. However, the rs167771 marker in DRD3, associated with ASD in a previous study, displayed a nominal association in our analysis (P = 0.023). Our data suggest that common allelic variants in the DDC gene may be involved in autism susceptibility.

Gene Transfer of Brain-derived Neurotrophic Factor (BDNF) Prevents Neurodegeneration Triggered by FXN Deficiency.

PubMed

Katsu-Jiménez, Yurika; Loría, Frida; Corona, Juan Carlos; Díaz-Nido, Javier

2016-05-01

Friedreich's ataxia is a predominantly neurodegenerative disease caused by recessive mutations that produce a deficiency of frataxin (FXN). Here, we have used a herpesviral amplicon vector carrying a gene encoding for brain-derived neurotrophic factor (BDNF) to drive its overexpression in neuronal cells and test for its effect on FXN-deficient neurons both in culture and in the mouse cerebellum in vivo. Gene transfer of BDNF to primary cultures of mouse neurons prevents the apoptosis which is triggered by the knockdown of FXN gene expression. This neuroprotective effect of BDNF is also observed in vivo in a viral vector-based knockdown mouse cerebellar model. The injection of a lentiviral vector carrying a minigene encoding for a FXN-specific short hairpin ribonucleic acid (shRNA) into the mouse cerebellar cortex triggers a FXN deficit which is accompanied by significant apoptosis of granule neurons as well as loss of calbindin in Purkinje cells. These pathological changes are accompanied by a loss of motor coordination of mice as assayed by the rota-rod test. Coinjection of a herpesviral vector encoding for BDNF efficiently prevents both the development of cerebellar neuropathology and the ataxic phenotype. These data demonstrate the potential therapeutic usefulness of neurotrophins like BDNF to protect FXN-deficient neurons from degeneration.

Direct Interaction between Scaffolding Proteins RACK1 and 14-3-3ζ Regulates Brain-derived Neurotrophic Factor (BDNF) Transcription*

PubMed Central

Neasta, Jérémie; Kiely, Patrick A.; He, Dao-Yao; Adams, David R.; O'Connor, Rosemary; Ron, Dorit

2012-01-01

RACK1 is a scaffolding protein that spatially and temporally regulates numerous signaling cascades. We previously found that activation of the cAMP signaling pathway induces the translocation of RACK1 to the nucleus. We further showed that nuclear RACK1 is required to promote the transcription of the brain-derived neurotrophic factor (BDNF). Here, we set out to elucidate the mechanism underlying cAMP-dependent RACK1 nuclear translocation and BDNF transcription. We identified the scaffolding protein 14-3-3ζ as a direct binding partner of RACK1. Moreover, we found that 14-3-3ζ was necessary for the cAMP-dependent translocation of RACK1 to the nucleus. We further observed that the disruption of RACK1/14-3-3ζ interaction with a peptide derived from the RACK1/14-3-3ζ binding site or shRNA-mediated 14-3-3ζ knockdown inhibited cAMP induction of BDNF transcription. Together, these data reveal that the function of nuclear RACK1 is mediated through its interaction with 14-3-3ζ. As RACK1 and 14-3-3ζ are two multifunctional scaffolding proteins that coordinate a wide variety of signaling events, their interaction is likely to regulate other essential cellular functions. PMID:22069327

Brain-derived neurotrophic factor inhibits glucose intolerance after cerebral ischemia

PubMed Central

Shu, Xiaoliang; Zhang, Yongsheng; Xu, Han; Kang, Kai; Cai, Donglian

2013-01-01

Brain-derived neurotrophic factor is associated with the insulin signaling pathway and glucose tabolism. We hypothesized that expression of brain-derived neurotrophic factor and its receptor may be involved in glucose intolerance following ischemic stress. To verify this hypothesis, this study aimed to observe the changes in brain-derived neurotrophic factor and tyrosine kinase B receptor expression in glucose metabolism-associated regions following cerebral ischemic stress in mice. At day 1 after middle cerebral artery occlusion, the expression levels of brain-derived neurotrophic factor were significantly decreased in the ischemic cortex, hypothalamus, liver, skeletal muscle, and pancreas. The expression levels of tyrosine kinase B receptor were decreased in the hypothalamus and liver, and increased in the skeletal muscle and pancreas, but remained unchanged in the cortex. Intrahypothalamic administration of brain-derived neurotrophic factor (40 ng) suppressed the decrease in insulin receptor and tyrosine-phosphorylated insulin receptor expression in the liver and skeletal muscle, and inhibited the overexpression of gluconeogenesis-associated phosphoenolpyruvate carboxykinase and glucose-6-phosphatase in the liver of cerebral ischemic mice. However, serum insulin levels remained unchanged. Our experimental findings indicate that brain-derived neurotrophic factor can promote glucose metabolism, reduce gluconeogenesis, and decrease blood glucose levels after cerebral ischemic stress. The low expression of brain-derived neurotrophic factor following cerebral ischemia may be involved in the development of glucose intolerance. PMID:25206547

Serum Brain-Derived Neurotrophic Factors in Taiwanese Patients with Drug-Naïve First-Episode Major Depressive Disorder: Effects of Antidepressants.

PubMed

Chiou, Yu-Jie; Huang, Tiao-Lai

2017-03-01

Brain-derived neurotrophic factors are known to be related to the psychopathology of major depressive disorder. However, studies focusing on drug-naïve first-episode patients are still rare. Over a 6-year period, we examined the serum brain-derived neurotrophic factors levels in patients with first-episode drug-naïve major depressive disorder and compared them with sex-matched healthy controls. We also investigated the relationships between serum brain-derived neurotrophic factors levels, suicidal behavior, and Hamilton Depression Rating Scale scores before and after a 4-week antidepressant treatment. The baseline serum brain-derived neurotrophic factors levels of 71 patients were significantly lower than those of the controls (P=.017), and the Hamilton Depression Rating Scale scores in 71 patients did not correlate with brain-derived neurotrophic factor levels. Brain-derived neurotrophic factor levels were significantly lower in 13 suicidal major depressive disorder patients than in 58 nonsuicidal major depressive disorder patients (P=.038). Among 41 followed-up patients, there was no alteration in serum brain-derived neurotrophic factors levels after treatment with antidepressants (P=.126). In receiver operating characteristic curve analysis of using pretreatment brain-derived neurotrophic factors to estimate the response to treatment, the area under the curve was 0.684. The most suitable cut-off point was 6.1 ng/mL (sensitivity=78.6%, specificity = 53.8%). Our data support the serum brain-derived neurotrophic factor levels in patients with drug-naïve first-episode major depressive disorder were lower than those in the healthy controls, and patients with pretreatment brain-derived neurotrophic factors >6.1 ng/mL were more likely to be responders. Although the relationship of our results to the mechanism of drug action and pathophysiology of depression remains unclear, the measure may have potential use as a predictor of response to treatment. In the future, it needs a large sample to prove these results. © The Author 2016. Published by Oxford University Press on behalf of CINP.

BDNF-Deficient Mice Show Reduced Psychosis-Related Behaviors Following Chronic Methamphetamine.

PubMed

Manning, Elizabeth E; Halberstadt, Adam L; van den Buuse, Maarten

2016-04-01

One of the most devastating consequences of methamphetamine abuse is increased risk of psychosis. Brain-derived neurotrophic factor has been implicated in both psychosis and neuronal responses to methamphetamine. We therefore examined persistent psychosis-like behavioral effects of methamphetamine in brain-derived neurotrophic factor heterozygous mice. Mice were chronically treated with methamphetamine from 6 to 9 weeks of age, and locomotor hyperactivity to an acute D-amphetamine challenge was tested in photocell cages after a 2-week withdrawal period. Methamphetamine-treated wild-type mice, but not brain-derived neurotrophic factor heterozygous mice, showed locomotor sensitization to acute 3mg/kg D-amphetamine. Qualitative analysis of exploration revealed tolerance to D-amphetamine effects on entropy in methamphetamine-treated brain-derived neurotrophic factor heterozygous mice, but not wild-type mice. Chronic methamphetamine exposure induces contrasting profiles of behavioral changes in wild-type and brain-derived neurotrophic factor heterozygous mice, with attenuation of behaviors relevant to psychosis in methamphetamine-treated brain-derived neurotrophic factor heterozygous mice. This suggests that brain-derived neurotrophic factor signalling changes may contribute to development of psychosis in methamphetamine users. © The Author 2015. Published by Oxford University Press on behalf of CINP.

[The neurobiology of autism].

PubMed

Kotsopoulos, S

2007-07-01

The research effort on autism has for several years been intensive. Recent progress in this field is due mainly to the development of increasingly sophisticated visualizing assessment methods of the brain. Most of the evidence reported in this review requires further replication and elaboration by ongoing research. Evidence from volumetric studies indicates that the brain of the child with autism deviates from normal paths at the early stages of development showing excessive growth during the first year and a half involving the hemispheres and the cerebellum. Post mortem studies have shown neuron abnormalities in the frontal and temporal cortex and the cerebellum. Studies using diffusion tensor imaging, an fMRI based method, have shown disruptions between white and grey matter in several areas of the hemispheres. Other studies investigating activation of the cortex showed lack of synchrony and coordination between anterior and posterior areas of the hemispheres. It has been suggested that the deviation in brain development in autism consists of excessive numbers of neurons which cause the cytoarchitectural deviation. A theory suggesting that the basic deficit in autism is due to dysfunction of the "mirror neuron system" requires further substantiation. The aetiology of autism is not known although risk factors have been identified. Predominant among them are genetic influences. The search is currently intensive for an understanding of the pathogenesis of the pathological deviation in the development of the brain in autism. Neurotrophic factors which determine the developmental steps of the brain are examined such as serotonin, brain-derived neurotrophic factor (BDNF), the neuropeptide reelin, neuroligines and others. There is evidence of some involvement of these factors with autism but it is still far from clear how they do interact with one another and how they lead to the pathological deviations observed in autism. The neurotrophic factors are evidently coded by genes which are being examined by geneticists. It has also been suggested that autoimmune responses while interacting with neurotrophic factors may be important for the autistic deviation in brain development. Limitations may exist in the interpretation of the study results on which the present review was based. These are probably due to inconsistencies among studies related to variability in the severity of the disorders and age among subjects, presence or not of mental retardation, differing assessment methods.

Optimizing neurotrophic factor combinations for neurite outgrowth

NASA Astrophysics Data System (ADS)

Deister, C.; Schmidt, C. E.

2006-06-01

Most neurotrophic factors are members of one of three families: the neurotrophins, the glial cell-line derived neurotrophic factor family ligands (GFLs) and the neuropoietic cytokines. Each family activates distinct but overlapping cellular pathways. Several studies have shown additive or synergistic interactions between neurotrophic factors from different families, though generally only a single combination has been studied. Because of possible interactions between the neurotrophic factors, the optimum concentration of a factor in a mixture may differ from the optimum when applied individually. Additionally, the effect of combinations of neurotrophic factors from each of the three families on neurite extension is unclear. This study examines the effects of several combinations of the neurotrophin nerve growth factor (NGF), the GFL glial cell-line derived neurotrophic factor (GDNF) and the neuropoietic cytokine ciliary neurotrophic factor (CNTF) on neurite outgrowth from young rat dorsal root ganglion (DRG) explants. The combination of 50 ng ml-1 NGF and 10 ng ml-1 of each GDNF and CNTF induced the highest level of neurite outgrowth at a 752 ± 53% increase over untreated DRGs and increased the longest neurite length to 2031 ± 97 µm compared to 916 ± 64 µm for untreated DRGs. The optimum concentrations of the three factors applied in combination corresponded to the optimum concentration of each factor when applied individually. These results indicate that the efficacy of future therapies for nerve repair would be enhanced by the controlled release of a combination of neurotrophins, GFLs and neuropoietic cytokines at higher concentrations than used in previous conduit designs.

NTS-polyplex: A potential nanocarrier for neurotrophic therapy of Parkinson’s disease

PubMed Central

Martinez-Fong, Daniel; Bannon, Michael J.; Trudeau, Louis-Eric; Gonzalez-Barrios, Juan A.; Arango-Rodriguez, Martha L.; Hernandez-Chan, Nancy G.; Reyes-Corona, David; Armendáriz-Borunda, Juan; Navarro-Quiroga, Ivan

2012-01-01

Nanomedicine has focused on targeted neurotrophic gene delivery to the brain as a strategy to stop and reverse neurodegeneration in Parkinson’s disease. Because of improved transfection ability, synthetic nanocarriers have become candidates for neurotrophic therapy. Neurotensin (NTS)-polyplex is a “Trojan horse” synthetic nanocarrier system that enters dopaminergic neurons through NTS receptor internalization to deliver a genetic cargo. The success of preclinical studies with different neurotrophic genes supports the possibility of using NTS-polyplex in nanomedicine. In this review, we describe the mechanism of NTS-polyplex transfection. We discuss the concept that an effective neurotrophic therapy requires a simultaneous effect on the axon terminals and soma of the remaining dopaminergic neurons. We also discuss the future of this strategy for the treatment of Parkinson’s disease. PMID:22406187

Trophic and neurotrophic factors in human pituitary adenomas (Review).

PubMed

Spoletini, Marialuisa; Taurone, Samanta; Tombolini, Mario; Minni, Antonio; Altissimi, Giancarlo; Wierzbicki, Venceslao; Giangaspero, Felice; Parnigotto, Pier Paolo; Artico, Marco; Bardella, Lia; Agostinelli, Enzo; Pastore, Francesco Saverio

2017-10-01

The pituitary gland is an organ that functionally connects the hypothalamus with the peripheral organs. The pituitary gland is an important regulator of body homeostasis during development, stress, and other processes. Pituitary adenomas are a group of tumors arising from the pituitary gland: they may be subdivided in functional or non-functional, depending on their hormonal activity. Some trophic and neurotrophic factors seem to play a key role in the development and maintenance of the pituitary function and in the regulation of hypothalamo-pituitary-adrenocortical axis activity. Several lines of evidence suggest that trophic and neurotrophic factors may be involved in pituitary function, thus suggesting a possible role of the trophic and neurotrophic factors in the normal development of pituitary gland and in the progression of pituitary adenomas. Additional studies might be necessary to better explain the biological role of these molecules in the development and progression of this type of tumor. In this review, in light of the available literature, data on the following neurotrophic factors are discussed: ciliary neurotrophic factor (CNTF), transforming growth factors β (TGF‑β), glial cell line-derived neurotrophic factor (GDNF), nerve growth factor (NGF), vascular endothelial growth factor (VEGF), vascular endothelial growth inhibitor (VEGI), fibroblast growth factors (FGFs) and epidermal growth factor (EGF) which influence the proliferation and growth of pituitary adenomas.

Neurotrophic factor intervention restores auditory function in deafened animals

NASA Astrophysics Data System (ADS)

Shinohara, Takayuki; Bredberg, Göran; Ulfendahl, Mats; Pyykkö, Ilmari; Petri Olivius, N.; Kaksonen, Risto; Lindström, Bo; Altschuler, Richard; Miller, Josef M.

2002-02-01

A primary cause of deafness is damage of receptor cells in the inner ear. Clinically, it has been demonstrated that effective functionality can be provided by electrical stimulation of the auditory nerve, thus bypassing damaged receptor cells. However, subsequent to sensory cell loss there is a secondary degeneration of the afferent nerve fibers, resulting in reduced effectiveness of such cochlear prostheses. The effects of neurotrophic factors were tested in a guinea pig cochlear prosthesis model. After chemical deafening to mimic the clinical situation, the neurotrophic factors brain-derived neurotrophic factor and an analogue of ciliary neurotrophic factor were infused directly into the cochlea of the inner ear for 26 days by using an osmotic pump system. An electrode introduced into the cochlea was used to elicit auditory responses just as in patients implanted with cochlear prostheses. Intervention with brain-derived neurotrophic factor and the ciliary neurotrophic factor analogue not only increased the survival of auditory spiral ganglion neurons, but significantly enhanced the functional responsiveness of the auditory system as measured by using electrically evoked auditory brainstem responses. This demonstration that neurotrophin intervention enhances threshold sensitivity within the auditory system will have great clinical importance for the treatment of deaf patients with cochlear prostheses. The findings have direct implications for the enhancement of responsiveness in deafferented peripheral nerves.

BDNF val66met Polymorphism Affects Aging of Multiple Types of Memory

PubMed Central

Kennedy, Kristen M.; Reese, Elizabeth D.; Horn, Marci M.; Sizemore, April N.; Unni, Asha K.; Meerbrey, Michael E.; Kalich, Allan G.; Rodrigue, Karen M.

2014-01-01

The BDNF val66met polymorphism (rs6265) influences activity-dependent secretion of brain-derived neurotrophic factor in the synapse, which is crucial for learning and memory. Individuals homozygous or heterozygous for the met allele have lower BDNF secretion than val homozygotes and may be at risk for reduced declarative memory performance, but it remains unclear which types of declarative memory may be affected and how aging of memory across the lifespan is impacted by the BDNF val66met polymorphism. This cross-sectional study investigated the effects of BDNF polymorphism on multiple indices of memory (item, associative, prospective, subjective complaints) in a lifespan sample of 116 healthy adults aged 20-93 years. Advancing age showed a negative effect on item, associative and prospective memory, but not on subjective memory complaints. For item and prospective memory, there were significant age x BDNF group interactions, indicating the adverse effect of age on memory performance across the lifespan was much stronger in the BDNF met carriers than for the val homozygotes. BDNF met carriers also endorsed significantly greater subjective memory complaints, regardless of age, and showed a trend (p < .07) toward poorer associative memory performance compared to val homozygotes. These results suggest that genetic predisposition to the availability of brain-derived neurotrophic factor, by way of the BDNF val66met polymorphism, exerts an influence on multiple indices of episodic memory – in some cases in all individuals regardless of age (subjective memory and perhaps associative memory), in others as an exacerbation of age-related differences in memory across the lifespan (item and prospective memory). PMID:25264352

Early Downregulation of p75NTR by Genetic and Pharmacological Approaches Delays the Onset of Motor Deficits and Striatal Dysfunction in Huntington's Disease Mice.

PubMed

Suelves, Nuria; Miguez, Andrés; López-Benito, Saray; Barriga, Gerardo García-Díaz; Giralt, Albert; Alvarez-Periel, Elena; Arévalo, Juan Carlos; Alberch, Jordi; Ginés, Silvia; Brito, Verónica

2018-05-27

Deficits in striatal brain-derived neurotrophic factor (BDNF) delivery and/or BDNF/tropomyosin receptor kinase B (TrkB) signaling may contribute to neurotrophic support reduction and selective early degeneration of striatal medium spiny neurons in Huntington's disease (HD). Furthermore, we and others have demonstrated that TrkB/p75 NTR imbalance in vitro increases the vulnerability of striatal neurons to excitotoxic insults and induces corticostriatal synaptic alterations. We have now expanded these studies by analyzing the consequences of BDNF/TrkB/p75 NTR imbalance in the onset of motor behavior and striatal neuropathology in HD mice. Our findings demonstrate for the first time that the onset of motor coordination abnormalities, in a full-length knock-in HD mouse model (KI), correlates with the reduction of BDNF and TrkB levels, along with an increase in p75 NTR expression. Genetic normalization of p75 NTR expression in KI mutant mice delayed the onset of motor deficits and striatal neuropathology, as shown by restored levels of striatal-enriched proteins and dendritic spine density and reduced huntingtin aggregation. We found that the BDNF/TrkB/p75 NTR imbalance led to abnormal BDNF signaling, manifested as a diminished activation of TrkB-phospholipase C-gamma pathway but upregulation of c-Jun kinase pathway. Moreover, we confirmed the contribution of the proper balance of BDNF/TrkB/p75 NTR on HD pathology by a pharmacological approach using fingolimod. We observed that chronic infusion of fingolimod normalizes p75 NTR levels, which is likely to improve motor coordination and striatal neuropathology in HD transgenic mice. We conclude that downregulation of p75 NTR expression can delay disease progression suggesting that therapeutic approaches aimed to restore the balance between BDNF, TrkB, and p75 NTR could be promising to prevent motor deficits in HD.

BBB-Permeable, Neuroprotective, and Neurotrophic Polysaccharide, Midi-GAGR.

PubMed

Makani, Vishruti; Jang, Yong-Gil; Christopher, Kevin; Judy, Wesley; Eckstein, Jacob; Hensley, Kenneth; Chiaia, Nicolas; Kim, Dong-Shik; Park, Joshua

2016-01-01

An enormous amount of efforts have been poured to find an effective therapeutic agent for the treatment of neurodegenerative diseases including Alzheimer's disease (AD). Among those, neurotrophic peptides that regenerate neuronal structures and increase neuron survival show a promise in slowing neurodegeneration. However, the short plasma half-life and poor blood-brain-barrier (BBB)-permeability of neurotrophic peptides limit their in vivo efficacy. Thus, an alternative neurotrophic agent that has longer plasma half-life and better BBB-permeability has been sought for. Based on the recent findings of neuroprotective polysaccharides, we searched for a BBB-permeable neuroprotective polysaccharide among natural polysaccharides that are approved for human use. Then, we discovered midi-GAGR, a BBB-permeable, long plasma half-life, strong neuroprotective and neurotrophic polysaccharide. Midi-GAGR is a 4.7kD cleavage product of low acyl gellan gum that is approved by FDA for human use. Midi-GAGR protected rodent cortical neurons not only from the pathological concentrations of co-/post-treated free reactive radicals and Aβ42 peptide but also from activated microglial cells. Moreover, midi-GAGR showed a good neurotrophic effect; it enhanced neurite outgrowth and increased phosphorylated cAMP-responsive element binding protein (pCREB) in the nuclei of primary cortical neurons. Furthermore, intra-nasally administered midi-GAGR penetrated the BBB and exerted its neurotrophic effect inside the brain for 24 h after one-time administration. Midi-GAGR appears to activate fibroblast growth factor receptor 1 (FGFR1) and its downstream neurotrophic signaling pathway for neuroprotection and CREB activation. Additionally, 14-day intranasal administration of midi-GAGR not only increased neuronal activity markers but also decreased hyperphosphorylated tau, a precursor of neurofibrillary tangle, in the brains of the AD mouse model, 3xTg-AD. Taken together, midi-GAGR with good BBB-permeability, long plasma half-life, and strong neuroprotective and neurotrophic effects has a great therapeutic potential for the treatment of neurodegenerative diseases, especially AD.

BBB-Permeable, Neuroprotective, and Neurotrophic Polysaccharide, Midi-GAGR

PubMed Central

Makani, Vishruti; Jang, Yong-gil; Christopher, Kevin; Judy, Wesley; Eckstein, Jacob; Hensley, Kenneth; Chiaia, Nicolas; Kim, Dong-Shik; Park, Joshua

2016-01-01

An enormous amount of efforts have been poured to find an effective therapeutic agent for the treatment of neurodegenerative diseases including Alzheimer’s disease (AD). Among those, neurotrophic peptides that regenerate neuronal structures and increase neuron survival show a promise in slowing neurodegeneration. However, the short plasma half-life and poor blood-brain-barrier (BBB)-permeability of neurotrophic peptides limit their in vivo efficacy. Thus, an alternative neurotrophic agent that has longer plasma half-life and better BBB-permeability has been sought for. Based on the recent findings of neuroprotective polysaccharides, we searched for a BBB-permeable neuroprotective polysaccharide among natural polysaccharides that are approved for human use. Then, we discovered midi-GAGR, a BBB-permeable, long plasma half-life, strong neuroprotective and neurotrophic polysaccharide. Midi-GAGR is a 4.7kD cleavage product of low acyl gellan gum that is approved by FDA for human use. Midi-GAGR protected rodent cortical neurons not only from the pathological concentrations of co-/post-treated free reactive radicals and Aβ42 peptide but also from activated microglial cells. Moreover, midi-GAGR showed a good neurotrophic effect; it enhanced neurite outgrowth and increased phosphorylated cAMP-responsive element binding protein (pCREB) in the nuclei of primary cortical neurons. Furthermore, intra-nasally administered midi-GAGR penetrated the BBB and exerted its neurotrophic effect inside the brain for 24 h after one-time administration. Midi-GAGR appears to activate fibroblast growth factor receptor 1 (FGFR1) and its downstream neurotrophic signaling pathway for neuroprotection and CREB activation. Additionally, 14-day intranasal administration of midi-GAGR not only increased neuronal activity markers but also decreased hyperphosphorylated tau, a precursor of neurofibrillary tangle, in the brains of the AD mouse model, 3xTg-AD. Taken together, midi-GAGR with good BBB-permeability, long plasma half-life, and strong neuroprotective and neurotrophic effects has a great therapeutic potential for the treatment of neurodegenerative diseases, especially AD. PMID:26939023

Fingolimod inhibits brain atrophy and promotes brain-derived neurotrophic factor in an animal model of multiple sclerosis.

PubMed

Smith, Paul A; Schmid, Cindy; Zurbruegg, Stefan; Jivkov, Magali; Doelemeyer, Arno; Theil, Diethilde; Dubost, Valérie; Beckmann, Nicolau

2018-05-15

Longitudinal brain atrophy quantification is a critical efficacy measurement in multiple sclerosis (MS) clinical trials and the determination of No Evidence of Disease Activity (NEDA). Utilising fingolimod as a clinically validated therapy we evaluated the use of repeated brain tissue volume measures during chronic experimental autoimmune encephalomyelitis (EAE) as a new preclinical efficacy measure. Brain volume changes were quantified using magnetic resonance imaging (MRI) at 7 Tesla and correlated to treatment-induced brain derived neurotrophic factor (BDNF) measured in blood, cerebrospinal fluid, spinal cord and brain. Serial brain MRI measurements revealed slow progressive brain volume loss in vehicle treated EAE mice despite a stable clinical score. Fingolimod (1 mg/kg) significantly ameliorated brain tissue atrophy in the cerebellum and striatum when administered from established EAE disease onwards. Fingolimod-dependent tissue preservation was associated with induction of BDNF specifically within the brain and co-localized with neuronal soma. In contrast, therapeutic teriflunomide (3 mg/kg) treatment failed to inhibit CNS autoimmune mediated brain degeneration. Finally, weekly anti-IL-17A antibody (15 mg/kg) treatment was highly efficacious and preserved whole brain, cerebellum and striatum volume. Fingolimod-mediated BDNF increases within the CNS may contribute to limiting progressive tissue loss during chronic neuroinflammation. Copyright © 2018 Elsevier B.V. All rights reserved.

Modulation of neurotrophic signaling pathways by polyphenols

PubMed Central

Moosavi, Fatemeh; Hosseini, Razieh; Saso, Luciano; Firuzi, Omidreza

2016-01-01

Polyphenols are an important class of phytochemicals, and several lines of evidence have demonstrated their beneficial effects in the context of a number of pathologies including neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. In this report, we review the studies on the effects of polyphenols on neuronal survival, growth, proliferation and differentiation, and the signaling pathways involved in these neurotrophic actions. Several polyphenols including flavonoids such as baicalein, daidzein, luteolin, and nobiletin as well as nonflavonoid polyphenols such as auraptene, carnosic acid, curcuminoids, and hydroxycinnamic acid derivatives including caffeic acid phentyl ester enhance neuronal survival and promote neurite outgrowth in vitro, a hallmark of neuronal differentiation. Assessment of underlying mechanisms, especially in PC12 neuronal-like cells, reveals that direct agonistic effect on tropomyosin receptor kinase (Trk) receptors, the main receptors of neurotrophic factors including nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) explains the action of few polyphenols such as 7,8-dihydroxyflavone. However, several other polyphenolic compounds activate extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K)/Akt pathways. Increased expression of neurotrophic factors in vitro and in vivo is the mechanism of neurotrophic action of flavonoids such as scutellarin, daidzein, genistein, and fisetin, while compounds like apigenin and ferulic acid increase cyclic adenosine monophosphate response element-binding protein (CREB) phosphorylation. Finally, the antioxidant activity of polyphenols reflected in the activation of Nrf2 pathway and the consequent upregulation of detoxification enzymes such as heme oxygenase-1 as well as the contribution of these effects to the neurotrophic activity have also been discussed. In conclusion, a better understanding of the neurotrophic effects of polyphenols and the concomitant modulations of signaling pathways is useful for designing more effective agents for management of neurodegenerative diseases. PMID:26730179

Up-regulation of neurotrophic factors by cinnamon and its metabolite sodium benzoate: therapeutic implications for neurodegenerative disorders.

PubMed

Jana, Arundhati; Modi, Khushbu K; Roy, Avik; Anderson, John A; van Breemen, Richard B; Pahan, Kalipada

2013-06-01

This study underlines the importance of cinnamon, a widely-used food spice and flavoring material, and its metabolite sodium benzoate (NaB), a widely-used food preservative and a FDA-approved drug against urea cycle disorders in humans, in increasing the levels of neurotrophic factors [e.g., brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3)] in the CNS. NaB, but not sodium formate (NaFO), dose-dependently induced the expression of BDNF and NT-3 in primary human neurons and astrocytes. Interestingly, oral administration of ground cinnamon increased the level of NaB in serum and brain and upregulated the levels of these neurotrophic factors in vivo in mouse CNS. Accordingly, oral feeding of NaB, but not NaFO, also increased the level of these neurotrophic factors in vivo in the CNS of mice. NaB induced the activation of protein kinase A (PKA), but not protein kinase C (PKC), and H-89, an inhibitor of PKA, abrogated NaB-induced increase in neurotrophic factors. Furthermore, activation of cAMP response element binding (CREB) protein, but not NF-κB, by NaB, abrogation of NaB-induced expression of neurotrophic factors by siRNA knockdown of CREB and the recruitment of CREB and CREB-binding protein to the BDNF promoter by NaB suggest that NaB exerts its neurotrophic effect through the activation of CREB. Accordingly, cinnamon feeding also increased the activity of PKA and the level of phospho-CREB in vivo in the CNS. These results highlight a novel neutrophic property of cinnamon and its metabolite NaB via PKA - CREB pathway, which may be of benefit for various neurodegenerative disorders.

ProBDNF inhibits collective migration and chemotaxis of rat Schwann cells.

PubMed

Ding, You-Quan; Li, Xuan-Yang; Xia, Guan-Nan; Ren, Hong-Yi; Zhou, Xin-Fu; Su, Bing-Yin; Qi, Jian-Guo

2016-10-01

Schwann cell migration, including collective migration and chemotaxis, is essential for the formation of coordinate interactions between Schwann cells and axons during peripheral nerve development and regeneration. Moreover, limited migration of Schwann cells imposed a serious obstacle on Schwann cell-astrocytes intermingling and spinal cord repair after Schwann cell transplantation into injured spinal cords. Recent studies have shown that mature brain-derived neurotrophic factor, a member of the neurotrophin family, inhibits Schwann cell migration. The precursor form of brain-derived neurotrophic factor, proBDNF, was expressed in the developing or degenerating peripheral nerves and the injured spinal cords. Since "the yin and yang of neurotrophin action" has been established as a common sense, proBDNF would be expected to promote Schwann cell migration. However, we found, in the present study, that exogenous proBDNF also inhibited in vitro collective migration and chemotaxis of RSC 96 cells, a spontaneously immortalized rat Schwann cell line. Moreover, proBDNF suppressed adhesion and spreading of those cells. At molecular level, proBDNF inhibits F-actin polymerization and focal adhesion dynamics in cultured RSC 96 cells. Therefore, our results suggested a special case against the classical opinion of "the yin and yang of neurotrophin action" and implied that proBDNF might modulate peripheral nerve development or regeneration and spinal cord repair through perturbing native or transplanted Schwann cell migration. Copyright © 2016 Elsevier Ltd. All rights reserved.

Dynamical modelling of coordinated multiple robot systems

NASA Technical Reports Server (NTRS)

Hayati, Samad

1987-01-01

The state of the art in the modeling of the dynamics of coordinated multiple robot manipulators is summarized and various problems related to this subject are discussed. It is recognized that dynamics modeling is a component used in the design of controllers for multiple cooperating robots. As such, the discussion addresses some problems related to the control of multiple robots. The techniques used to date in the modeling of closed kinematic chains are summarized. Various efforts made to date for the control of coordinated multiple manipulators is summarized.

Plasma brain-derived neurotrophic factor in women after bariatric surgery: a pilot study.

PubMed

Merhi, Zaher O; Minkoff, Howard; Lambert-Messerlian, Geralyn M; Macura, Jerzy; Feldman, Joseph; Seifer, David B

2009-04-01

Eighteen morbidly obese women had plasma brain-derived neurotrophic factor (BDNF) measured before bariatric surgery and 3 months postoperatively. We analyzed plasma BDNF levels in all the participants then subdivided according to menopausal status and type of surgery. Brain-derived neurotrophic factor decreased significantly in all the participants and in the premenopausal group when looked at in isolation.

Protective effects of brain-derived neurotrophic factor on the noise-damaged cochlear spiral ganglion.

PubMed

Zhai, S-Q; Guo, W; Hu, Y-Y; Yu, N; Chen, Q; Wang, J-Z; Fan, M; Yang, W-Y

2011-05-01

To explore the protective effects of brain-derived neurotrophic factor on the noise-damaged cochlear spiral ganglion. Recombinant adenovirus brain-derived neurotrophic factor vector, recombinant adenovirus LacZ and artificial perilymph were prepared. Guinea pigs with audiometric auditory brainstem response thresholds of more than 75 dB SPL, measured seven days after four hours of noise exposure at 135 dB SPL, were divided into three groups. Adenovirus brain-derived neurotrophic factor vector, adenovirus LacZ and perilymph were infused into the cochleae of the three groups, variously. Eight weeks later, the cochleae were stained immunohistochemically and the spiral ganglion cells counted. The auditory brainstem response threshold recorded before and seven days after noise exposure did not differ significantly between the three groups. However, eight weeks after cochlear perfusion, the group receiving brain-derived neurotrophic factor had a significantly decreased auditory brainstem response threshold and increased spiral ganglion cell count, compared with the adenovirus LacZ and perilymph groups. When administered via cochlear infusion following noise damage, brain-derived neurotrophic factor appears to improve the auditory threshold, and to have a protective effect on the spiral ganglion cells.

Neurotrophic factors and corneal nerve regeneration

PubMed Central

Sacchetti, Marta; Lambiase, Alessandro

2017-01-01

The cornea has unique features that make it a useful model for regenerative medicine studies. It is an avascular, transparent, densely innervated tissue and any pathological changes can be easily detected by slit lamp examination. Corneal sensitivity is provided by the ophthalmic branch of the trigeminal nerve that elicits protective reflexes such as blinking and tearing and exerts trophic support by releasing neuromediators and growth factors. Corneal nerves are easily evaluated for both function and morphology using standard instruments such as corneal esthesiometer and in vivo confocal microscope. All local and systemic conditions that are associated with damage of the trigeminal nerve cause the development of neurotrophic keratitis, a rare degenerative disease. Neurotrophic keratitis is characterized by impairment of corneal sensitivity associated with development of persistent epithelial defects that may progress to corneal ulcer, melting and perforation. Current neurotrophic keratitis treatments aim at supporting corneal healing and preventing progression of corneal damage. Novel compounds able to stimulate corneal nerve recovery are in advanced development stage. Among them, nerve growth factor eye drops showed to be safe and effective in stimulating corneal healing and improving corneal sensitivity in patients with neurotrophic keratitis. Neurotrophic keratitis represents an useful model to evaluate in clinical practice novel neuro-regenerative drugs. PMID:28966630

Growth factor treatment of demyelinating disease: at last, a leap into the light.

PubMed

Ransohoff, Richard M; Howe, Charles L; Rodriguez, Moses

2002-11-01

Researchers seeking treatments for multiple sclerosis (MS) have long dreamed of using neurotrophic factors to enhance remyelination. Previous attempts to apply trophic support for oligodendrocytes in experimental demyelination uniformly produced complicated outcomes that reflected unexpected effects on immune or inflammatory responses and could be interpreted only with caution. Now, two recent publications have demonstrated convincingly that cytokines of the interleukin (IL)-6 superfamily can ameliorate experimental autoimmune encephalomyelitis and promote oligodendrocyte survival, without demonstrable effect on inflammation or immune responses.

A Single Brain-Derived Neurotrophic Factor Infusion into the Dorsomedial Prefrontal Cortex Attenuates Cocaine Self-Administration-Induced Phosphorylation of Synapsin in the Nucleus Accumbens during Early Withdrawal

PubMed Central

Sun, Wei-Lun; Eisenstein, Sarah A.; Zelek-Molik, Agnieszka

2015-01-01

Background: Dysregulation in the prefrontal cortex-nucleus accumbens pathway has been implicated in cocaine addiction. We have previously demonstrated that one intra-dorsomedial prefrontal cortex brain-derived neurotrophic factor (BDNF) infusion immediately following the last cocaine self-administration session caused a long-lasting inhibition of cocaine-seeking and normalized the cocaine-induced disturbance of glutamate transmission in the nucleus accumbens after extinction and a cocaine prime. However, the molecular mechanism mediating the brain-derived neurotrophic factor effect on cocaine-induced alterations in extracellular glutamate levels is unknown. Methods: In the present study, we determined the effects of brain-derived neurotrophic factor on cocaine-induced changes in the phosphorylation of synapsin (p-synapsin), a family of presynaptic proteins that mediate synaptic vesicle mobilization, in the nucleus accumbens during early withdrawal. Results: Two hours after cocaine self-administration, p-synapsin Ser9 and p-synapsin Ser62/67, but not p-synapsin Ser603, were increased in the nucleus accumbens. At 22 hours, only p-synapsin Ser9 was still elevated. Elevations at both time points were attenuated by an intra-dorsomedial prefrontal cortex brain-derived neurotrophic factor infusion immediately after the end of cocaine self-administration. Brain-derived neurotrophic factor also reduced cocaine self-administration withdrawal-induced phosphorylation of the protein phosphatase 2A C-subunit, suggesting that brain-derived neurotrophic factor disinhibits protein phosphatase 2A C-subunit, consistent with p-synapsin Ser9 dephosphorylation. Further, co-immunoprecipitation demonstrated that protein phosphatase 2A C-subunit and synapsin are associated in a protein-protein complex that was reduced after 2 hours of withdrawal from cocaine self-administration and reversed by brain-derived neurotrophic factor. Conclusions: Taken together, these findings demonstrate that brain-derived neurotrophic factor normalizes the cocaine self-administration–induced elevation of p-synapsin in nucleus accumbens that may underlie a disturbance in the probability of neurotransmitter release or represent a compensatory neuroadaptation in response to the hypofunction within the prefrontal cortex-nucleus accumbens pathway during cocaine withdrawal. PMID:25522393

The protective effects of resveratrol on Schwann cells with toxicity induced by ethanol in vitro.

PubMed

Yuan, Hongtu; Zhang, Jingfen; Liu, Huaxiang; Li, Zhenzhong

2013-09-01

Schwann cells (SCs) are the myelin forming cells in the peripheral nervous system, they play a key role in the pathology of various polyneuropathies and provide trophic support to axons via expression of various neurotrophic factors, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF). Ethanol (EtOH) adversely affected both SCs proliferation and myelin formation in culture. Resveratrol (Res) has been shown to regulate many cellular processes and to display multiple protective and therapeutic effects. Whether Res has protective effects on SCs with EtOH-induced toxicity is still unclear. The protective efficacy of Res on EtOH-treated SCs in vitro was investigated in the present study. Res improved cell viability of the EtOH-treated SCs. Hoechst 33342 staining and terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate nick-end labeling analysis showed that the EtOH-induced apoptosis was inhibited by Res. The effects of Res were blocked by the 5'-adenosine monophosphate-activated protein kinase inhibitor Compound C and the silencing information regulator T1 inhibitor nicotinamide. Res could increase the mRNA and protein levels of BDNF and GDNF in the EtOH-treated SCs. However, the EtOH-induced increase of NGF in the SCs is inhibited by Res. The data from the present study indicate that Res protects SCs from EtOH-induced cell death and regulates the expression of neurotrophicfactors. Res and its derivative may be effective for the treatment of neuropathic diseases induced by EtOH. Copyright © 2013 Elsevier Ltd. All rights reserved.

Fluoxetine Ameliorates Behavioral and Neuropathological Deficits in a Transgenic Model Mouse of α-synucleinopathy

PubMed Central

Ubhi, Kiren; Inglis, Chandra; Mante, Michael; Patrick, Christina; Adame, Anthony; Spencer, Brian; Rockenstein, Edward; May, Verena; Winkler, Juergen; Masliah, Eliezer

2013-01-01

The term α-synucleinopathies refers to a group of age-related neurological disorders including Parkinson’s disease (PD), Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA) that display an abnormal accumulation of alpha-synuclein (α-syn). In contrast to the neuronal α-syn accumulation observed in PD and DLB, MSA is characterized by a widespread oligodendrocytic α-syn accumulation. Transgenic mice expressing human α-syn under the oligodendrocyte-specific myelin basic protein promoter (MBP1-hαsyn tg mice) model many of the behavioral and neuropathological alterations observed in MSA. Fluoxetine, a selective serotonin reuptake inhibitor, has been shown to be protective in toxin-induced models of PD, however its effects in an in vivo transgenic model of α-synucleinopathy remain unclear. In this context, this study examined the effect of fluoxetine in the MBP1-hαsyn tg mice, a model of MSA. Fluoxetine adminstration ameliorated motor deficits in the MBP1-hαsyn tg mice, with a concomitant decrease in neurodegenerative pathology in the basal ganglia, neocortex and hippocampus. Fluoxetine adminstration also increased levels of the neurotrophic factors, GDNF (glial-derived neurotrophic factor) and BDNF (brain-derived neurotrophic factor) in the MBP1-hαsyn tg mice compared to vehicle-treated tg mice. This fluoxetine-induced increase in GDNF and BDNF protein levels was accompanied by activation of the ERK signaling pathway. The effects of fluoxetine adminstration on myelin and serotonin markers were also examined. Collectively these results indicate that fluoxetine may represent a novel therapeutic intervention for MSA and other neurodegenerative disorders. PMID:22281106

BDNF val66met polymorphism affects aging of multiple types of memory.

PubMed

Kennedy, Kristen M; Reese, Elizabeth D; Horn, Marci M; Sizemore, April N; Unni, Asha K; Meerbrey, Michael E; Kalich, Allan G; Rodrigue, Karen M

2015-07-01

The BDNF val66met polymorphism (rs6265) influences activity-dependent secretion of brain-derived neurotrophic factor in the synapse, which is crucial for learning and memory. Individuals homozygous or heterozygous for the met allele have lower BDNF secretion than val homozygotes and may be at risk for reduced declarative memory performance, but it remains unclear which types of declarative memory may be affected and how aging of memory across the lifespan is impacted by the BDNF val66met polymorphism. This cross-sectional study investigated the effects of BDNF polymorphism on multiple indices of memory (item, associative, prospective, subjective complaints) in a lifespan sample of 116 healthy adults aged 20-93 years. Advancing age showed a negative effect on item, associative and prospective memory, but not on subjective memory complaints. For item and prospective memory, there were significant age×BDNF group interactions, indicating the adverse effect of age on memory performance across the lifespan was much stronger in the BDNF met carriers than for the val homozygotes. BDNF met carriers also endorsed significantly greater subjective memory complaints, regardless of age, and showed a trend (p<.07) toward poorer associative memory performance compared to val homozygotes. These results suggest that genetic predisposition to the availability of brain-derived neurotrophic factor, by way of the BDNF val66met polymorphism, exerts an influence on multiple indices of episodic memory - in some cases in all individuals regardless of age (subjective memory and perhaps associative memory), in others as an exacerbation of age-related differences in memory across the lifespan (item and prospective memory). This article is part of a Special Issue entitled Memory & Aging. Copyright © 2014 Elsevier B.V. All rights reserved.

Fingolimod induces neuroprotective factors in human astrocytes.

PubMed

Hoffmann, Franziska S; Hofereiter, Johann; Rübsamen, Heike; Melms, Johannes; Schwarz, Sigrid; Faber, Hans; Weber, Peter; Pütz, Benno; Loleit, Verena; Weber, Frank; Hohlfeld, Reinhard; Meinl, Edgar; Krumbholz, Markus

2015-09-30

Fingolimod (FTY720) is the first sphingosine-1-phosphate (S1P) receptor modulator approved for the treatment of multiple sclerosis. The phosphorylated active metabolite FTY720-phosphate (FTY-P) interferes with lymphocyte trafficking. In addition, it accumulates in the CNS and reduces brain atrophy in multiple sclerosis (MS), and neuroprotective effects are hypothesized. Human primary astrocytes as well as human astrocytoma cells were stimulated with FTY-P or S1P. We analyzed gene expression by a genome-wide microarray and validated induced candidate genes by quantitative PCR (qPCR) and ELISA. To identify the S1P-receptor subtypes involved, we applied a membrane-impermeable S1P analog (dihydro-S1P), receptor subtype specific agonists and antagonists, as well as RNAi silencing. FTY-P induced leukemia inhibitory factor (LIF), interleukin 11 (IL11), and heparin-binding EGF-like growth factor (HBEGF) mRNA, as well as secretion of LIF and IL11 protein. In order to mimic an inflammatory milieu as observed in active MS lesions, we combined FTY-P application with tumor necrosis factor (TNF). In the presence of this key inflammatory cytokine, FTY-P synergistically induced LIF, HBEGF, and IL11 mRNA, as well as secretion of LIF and IL11 protein. TNF itself induced inflammatory, B-cell promoting, and antiviral factors (CXCL10, BAFF, MX1, and OAS2). Their induction was blocked by FTY-P. After continuous exposure of cells to FTY-P or S1P for up to 7 days, the extent of induction of neurotrophic factors and the suppression of TNF-induced inflammatory genes declined but was still detectable. The induction of neurotrophic factors was mediated via surface S1P receptors 1 (S1PR1) and 3 (S1PR3). We identified effects of FTY-P on astrocytes, namely induction of neurotrophic mediators (LIF, HBEGF, and IL11) and inhibition of TNF-induced inflammatory genes (CXCL10, BAFF, MX1, and OAS2). This supports the view that a part of the effects of fingolimod may be mediated via astrocytes.

Setting standards at the forefront of delivery system reform: aligning care coordination quality measures for multiple chronic conditions.

PubMed

DuGoff, Eva H; Dy, Sydney; Giovannetti, Erin R; Leff, Bruce; Boyd, Cynthia M

2013-01-01

The primary study objective is to assess how three major health reform care coordination initiatives (Accountable Care Organizations, Independence at Home, and Community-Based Care Transitions) measure concepts critical to care coordination for people with multiple chronic conditions. We find that there are major differences in quality measurement across these three large and politically important programs. Quality measures currently used or proposed for these new health reform-related programs addressing care coordination primarily capture continuity of care. Other key areas of care coordination, such as care transitions, patient-centeredness, and cross-cutting care across multiple conditions are infrequently addressed. The lack of a comprehensive and consistent measure set for care coordination will pose challenges for healthcare providers and policy makers who seek, respectively, to provide and reward well-coordinated care. In addition, this heterogeneity in measuring care coordination quality will generate new information, but will inhibit comparisons between these care coordination programs. © 2013 National Association for Healthcare Quality.

Setting Standards at the Forefront of Delivery System Reform: Aligning Care Coordination Quality Measures for Multiple Chronic Conditions

PubMed Central

DuGoff, Eva H.; Dy, Sydney; Giovannetti, Erin R.; Leff, Bruce; Boyd, Cynthia M.

2015-01-01

The primary study objective is to assess how three major health reform care coordination initiatives (Accountable Care Organizations, Independence at Home, and Community-based Care Transitions) measure concepts critical to care coordination for people with multiple chronic conditions. We find that there are major differences in quality measurement across these three large and politically important programs. Quality measures currently used or proposed for these new health reform-related programs addressing care coordination primarily capture continuity of care. Other key areas of care coordination, such as care transitions, patient-centeredness, and cross-cutting care across multiple conditions are infrequently addressed. The lack of a comprehensive and consistent measure set for care coordination will pose challenges for health care providers and policymakers who seek, respectively, to provide and reward well-coordinated care. In addition, this heterogeneity in measuring care coordination quality will generate new information, but will inhibit comparisons between these care coordination programs. PMID:24004040

Neurotrophic and neuroprotective potential of human limbus-derived mesenchymal stromal cells.

PubMed

Liang, Chang-Min; Weng, Shao-Ju; Tsai, Tung-Han; Li, I-Hsun; Lu, Pin-Hui; Ma, Kuo-Hsing; Tai, Ming-Cheng; Chen, Jiann-Torng; Cheng, Cheng-Yi; Huang, Yuahn-Sieh

2014-10-01

The purpose of this study was to examine neurotrophic and neuroprotective effects of limbus stroma-derived mesenchymal stromal cells (L-MSCs) on cortical neurons in vitro and in vivo. Cultured L-MSCs were characterized by flow cytometry and immunofluorescence through the use of specific MSC marker antibodies. Conditioned media were collected from normoxia- and hypoxia-treated L-MSCs to assess neurotrophic effects. Neuroprotective potentials were evaluated through the use of in vitro hypoxic cortical neuron culture and in vivo rat focal cerebral ischemia models. Neuronal morphology was confirmed by immunofluorescence with the use of anti-MAP2 antibody. Post-ischemic infarct volume and motor behavior were assayed by means of triphenyltetrazolium chloride staining and open-field testing, respectively. Human growth antibody arrays and enzyme-linked immunoassays were used to analyze trophic/growth factors contained in conditioned media. Isolated human L-MSCs highly expressed CD29, CD90 and CD105 but not CD34 and CD45. Mesenchymal lineage cell surface expression pattern and differentiation capacity were identical to MSCs derived form human bone marrow and adipose tissue. The L-MSC normoxic and hypoxic conditioned media both promoted neurite outgrowth in cultured cortical neurons. Hypoxic conditioned medium showed superior neurotrophic function and neuroprotective potential with reduced ischemic brain injury and improved functional recovery in rat focal cerebral ischemia models. Human growth factor arrays and enzyme-linked immunoassays measurements showed neuroprotective and growth-associated cytokines (vascular endothelial growth factor [VEGF], VEGFR3, brain-derived neurotrophic factor, insulin-like growth factor -2 and hepatocyte growth factor) contained in conditioned media. Hypoxic exposure caused VEGF and brain-derived neurotrophic factor upregulation, possibly contributing to neurotrophic and neuroprotective effects. L-MSCs can secrete various neurotrophic factors stimulating neurite outgrowth and protecting neurons against brain ischemic injury through paracrine mechanism. Copyright © 2014 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Alternative source of stem cells derived from human periodontal ligament: a new treatment for experimental autoimmune encephalomyelitis.

PubMed

Trubiani, Oriana; Giacoppo, Sabrina; Ballerini, Patrizia; Diomede, Francesca; Piattelli, Adriano; Bramanti, Placido; Mazzon, Emanuela

2016-01-04

Multiple sclerosis is a demyelinating disease mostly of autoimmune origin that affects and damages the central nervous system, leading to a disabling condition. The aim of the present study was to investigate whether administration of mesenchymal stem cells from human periodontal ligament (hPDLSCs) could ameliorate multiple sclerosis progression by exerting neuroprotective effects in an experimental model of autoimmune encephalomyelitis (EAE). EAE was induced by immunization with myelin oligodendroglial glycoprotein peptide (MOG)35-55 in C57BL/6 mice. After immunization, mice were observed every 48 hours for signs of EAE and weight loss. At the onset of disease, approximately 14 days after immunization, EAE mice were subjected to a single intravenous injection of hPDLSCs (10(6) cells/150 μl) into the tail vein. At the point of animal sacrifice on day 56 after EAE induction, spinal cord and brain tissues were collected in order to perform histological evaluation, immunohistochemistry and western blotting analysis. Achieved results reveal that treatment with hPDLSCs may exert neuroprotective effects against EAE, diminishing both clinical signs and histological score typical of the disease (lymphocytic infiltration and demyelination) probably through the production of neurotrophic factors (results focused on brain-derived neurotrophic factor and nerve growth factor expression). Furthermore, administration of hPDLSCs modulates expression of inflammatory key markers (tumor necrosis factor-α, interleukin (IL)-1β, IL-10, glial fibrillary acidic protein, Nrf2 and Foxp3), the release of CD4 and CD8α T cells, and the triggering of apoptotic death pathway (data shown for cleaved caspase 3, p53 and p21). In light of the achieved results, transplantation of hPDLSCs may represent a putative novel and helpful tool for multiple sclerosis treatment. These cells could have considerable implication for future therapies for multiple sclerosis and this study may represent the starting point for further investigations.

Vehicle coordinated transportation dispatching model base on multiple crisis locations

NASA Astrophysics Data System (ADS)

Tian, Ran; Li, Shanwei; Yang, Guoying

2018-05-01

Many disastrous events are often caused after unconventional emergencies occur, and the requirements of disasters are often different. It is difficult for a single emergency resource center to satisfy such requirements at the same time. Therefore, how to coordinate the emergency resources stored by multiple emergency resource centers to various disaster sites requires the coordinated transportation of emergency vehicles. In this paper, according to the problem of emergency logistics coordination scheduling, based on the related constraints of emergency logistics transportation, an emergency resource scheduling model based on multiple disasters is established.

Diverted organic synthesis (DOS): accessing a new, natural product inspired, neurotrophically active scaffold through an intramolecular Pauson-Khand reaction.

PubMed

Mehta, Goverdhan; Samineni, Ramesh; Srihari, Pabbaraja; Reddy, R Gajendra; Chakravarty, Sumana

2012-09-14

Drawing inspiration from the impressive neurotrophic activity exhibited by the natural product paecilomycine A, we have designed a new natural product-like scaffold employing an intramolecular Pauson-Khand reaction. Several compounds based on the new designer scaffold exhibited promising neurotrophic activity and are worthy of further biological evaluation. Our findings also highlight the importance of a DOS strategy in creating useful therapeutical leads.

Role of neurotrophins in the development and function of neural circuits that regulate energy homeostasis.

PubMed

Fargali, Samira; Sadahiro, Masato; Jiang, Cheng; Frick, Amy L; Indall, Tricia; Cogliani, Valeria; Welagen, Jelle; Lin, Wei-Jye; Salton, Stephen R

2012-11-01

Members of the neurotrophin family, including nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4/5, and other neurotrophic growth factors such as ciliary neurotrophic factor and artemin, regulate peripheral and central nervous system development and function. A subset of the neurotrophin-dependent pathways in the hypothalamus, brainstem, and spinal cord, and those that project via the sympathetic nervous system to peripheral metabolic tissues including brown and white adipose tissue, muscle and liver, regulate feeding, energy storage, and energy expenditure. We briefly review the role that neurotrophic growth factors play in energy balance, as regulators of neuronal survival and differentiation, neurogenesis, and circuit formation and function, and as inducers of critical gene products that control energy homeostasis.

Short-term ethanol exposure causes imbalanced neurotrophic factor allocation in the basal forebrain cholinergic system: a novel insight into understanding the initial processes of alcohol addiction.

PubMed

Miki, Takanori; Kusaka, Takashi; Yokoyama, Toshifumi; Ohta, Ken-ichi; Suzuki, Shingo; Warita, Katsuhiko; Jamal, Mostofa; Wang, Zhi-Yu; Ueki, Masaaki; Liu, Jun-Qian; Yakura, Tomiko; Tamai, Motoki; Sumitani, Kazunori; Hosomi, Naohisa; Takeuchi, Yoshiki

2014-02-01

Alcohol ingestion affects both motor and cognitive functions. One brain system that is influenced by ethanol is the basal forebrain (BF) cholinergic projection system, which projects to diverse neocortical and limbic areas. The BF is associated with memory and cognitive function. Our primary interest is the examination of how regions that receive BF cholinergic projections are influenced by short-term ethanol exposure through alterations in the mRNA levels of neurotrophic factors [nerve growth factor/TrkA, brain-derived neurotrophic factor/TrkB, and glial-derived neurotrophic factor (GDNF)/GDNF family receptor α1]. Male BALB/C mice were fed a liquid diet containing 5 % (v/v) ethanol. Pair-fed control mice were maintained on an identical liquid diet, except that the ethanol was isocalorically substituted with sucrose. Mice exhibiting signs of ethanol intoxication (stages 1-2) were used for real-time reverse transcription-polymerase chain reaction analyses. Among the BF cholinergic projection regions, decreased levels of GDNF mRNA and increased levels of TrkB mRNA were observed in the basal nucleus, and increased levels of TrkB mRNA were observed in the cerebral cortex. There were no significant alterations in the levels of expression of relevant neurotrophic factors in the septal nucleus and hippocampus. Given that neurotrophic factors function in retrograde/anterograde or autocrine/paracrine mechanisms and that BF cholinergic projection regions are neuroanatomically connected, these findings suggested that an imbalanced allocation of neurotrophic factor ligands and receptors is an initial phenomenon in alcohol addiction. The exact mechanisms underlying this phenomenon in the BF cholinergic system are unknown. However, our results provide a novel notion for the understanding of the initial processes in alcohol addiction.

Adult Stem Cell-Based Enhancement of Nerve Conduit for Peripheral Nerve Repair

DTIC Science & Technology

2017-10-01

neurotrophically activated cell types and conditioned media (via RT-PCR and ELISA of neurotrophic factors), followed by cell storage Specific objective 9...Mesenchymal Progenitor Cells (NI-MiMPCs) and Mesenchymal Stem Cells (MSCs), quantified via ELISA . MiMPCs and MSCs were cultured in neurotrophic induction...LIF, (E) osteonectin, and (F) clusterin. All ELISA results are expressed in pg/ml or ng/ml produced per million cells. Medium taken from NI-MiMPC

Sertoli Cells Avert Neuroinflammation-Induced Cell Death and Improve Motor Function and Striatal Atrophy in Rat Model of Huntington Disease.

PubMed

Ahmadi, Houssein; Boroujeni, Mahdi Eskandarian; Sadeghi, Yousef; Abdollahifar, Mohammad Amin; Khodagholi, Fariba; Meftahi, Gholam Houssein; Hadipour, Mohammadmehdi; Bayat, Amir-Hossein; Shaerzadeh, Fatemeh; Aliaghaei, Abbas

2018-05-01

Huntington's disease (HD) is a genetically heritable disorder, linked with continuing cell loss and degeneration mostly in the striatum. Currently, cell therapy approaches in HD have essentially been focused on replenishing or shielding cells lost over the period of the disease. Herein, we sought to explore the in vitro and in vivo efficacy of primary rat Sertoli cells (SCs) and their paracrine effect against oxidative stress with emphasis on HD. Initially, SCs were isolated and immunophenotypically characterized by positive expression of GATA4. Besides, synthesis of neurotrophic factors of glial cell-derived neurotrophic factor and VEGF by SCs were proved. Next, PC12 cells were exposed to hydrogen peroxide in the presence of conditioned media (CM) collected from SC (SC-CM) and cell viability and neuritogenesis were determined. Bilateral striatal implantation of SC in 3-nitropropionic acid (3-NP)-lesioned rat models was performed, and 1 month later, post-graft analysis was done. According to our in vitro results, the CM of SC protected PC12 cells against oxidative stress and remarkably augmented cell viability and neurite outgrowth. Moreover, grafted SCs survived, exhibited decreases in both gliosis and inflammatory cytokine levels, and ameliorated motor coordination and muscle activity, together with an increase in striatal volume as well as in dendritic length of the striatum in HD rats. In conclusion, our results indicate that SCs provide a supportive environment, with potential therapeutic benefits aimed at HD.

Neurotrophic Factors and Maternal Nutrition During Pregnancy.

PubMed

Dhobale, M

2017-01-01

Maternal nutrition is one of the major determinants of pregnancy outcome. It has been suggested that reduced intakes or lack of specific nutrients during pregnancy influences the length of gestation, proper placental and fetal growth during pregnancy. Maternal nutrition, particularly micronutrients such as folate and vitamin B 12 , and long-chain polyunsaturated fatty acids (LCPUFA) are the major determinants of the one carbon cycle and are suggested to be at the heart of intrauterine programming of diseases in adult life. LCPUFA play a key role in the normal feto-placental development, as well as in the development and functional maturation of the brain and central nervous system and also regulate the levels of neurotrophic factors. These neurotrophic factors are known to regulate the development of the placenta at the materno-fetal interface and act in a paracrine and endocrine manner. Neurotrophic factors like brain-derived neurotrophic factor and nerve growth factor are proteins involved in angiogenesis and potentiate the placental development. This chapter mainly focuses on micronutrients since they play a main physiological role during pregnancy. © 2017 Elsevier Inc. All rights reserved.

The Effects of Physical Exercise and Cognitive Training on Memory and Neurotrophic Factors.

PubMed

Heisz, Jennifer J; Clark, Ilana B; Bonin, Katija; Paolucci, Emily M; Michalski, Bernadeta; Becker, Suzanna; Fahnestock, Margaret

2017-11-01

This study examined the combined effect of physical exercise and cognitive training on memory and neurotrophic factors in healthy, young adults. Ninety-five participants completed 6 weeks of exercise training, combined exercise and cognitive training, or no training (control). Both the exercise and combined training groups improved performance on a high-interference memory task, whereas the control group did not. In contrast, neither training group improved on general recognition performance, suggesting that exercise training selectively increases high-interference memory that may be linked to hippocampal function. Individuals who experienced greater fitness improvements from the exercise training (i.e., high responders to exercise) also had greater increases in the serum neurotrophic factors brain-derived neurotrophic factor and insulin-like growth factor-1. These high responders to exercise also had better high-interference memory performance as a result of the combined exercise and cognitive training compared with exercise alone, suggesting that potential synergistic effects might depend on the availability of neurotrophic factors. These findings are especially important, as memory benefits accrued from a relatively short intervention in high-functioning young adults.

Laminar development of receptive fields, maps and columns in visual cortex: the coordinating role of the subplate.

PubMed

Grossberg, Stephen; Seitz, Aaron

2003-08-01

How is development of cortical maps in V1 coordinated across cortical layers to form cortical columns? Previous neural models propose how maps of orientation (OR), ocular dominance (OD), and related properties develop in V1. These models show how spontaneous activity, before eye opening, combined with correlation learning and competition, can generate maps similar to those found in vivo. These models have not discussed laminar architecture or how cells develop and coordinate their connections across cortical layers. This is an important problem since anatomical evidence shows that clusters of horizontal connections form, between iso-oriented regions, in layer 2/3 before being innervated by layer 4 afferents. How are orientations in different layers aligned before these connections form? Anatomical evidence demonstrates that thalamic afferents wait in the subplate for weeks before innervating layer 4. Other evidence shows that ablation of the cortical subplate interferes with the development of OR and OD columns. The model proposes how the subplate develops OR and OD maps, which then entrain and coordinate the development of maps in other lamina. The model demonstrates how these maps may develop in layer 4 by using a known transient subplate-to-layer 4 circuit as a teacher. The model subplate also guides the early clustering of horizontal connections in layer 2/3, and the formation of the interlaminar circuitry that forms cortical columns. It is shown how layer 6 develops and helps to stabilize the network when the subplate atrophies. Finally the model clarifies how brain-derived neurotrophic factor (BDNF) manipulations may influence cortical development.

BDNF in schizophrenia, depression and corresponding animal models.

PubMed

Angelucci, F; Brenè, S; Mathé, A A

2005-04-01

Understanding the etiology and pathogenesis schizophrenia and depression is a major challenge facing psychiatry. One hypothesis is that these disorders are secondary to a malfunction of neurotrophic factors. Inappropriate neurotrophic support during brain development could lead to structural disorganisation in which neuronal networks are established in a nonoptimal manner. Inadequate neurotrophic support in adult individuals could ultimately be an underlying mechanism leading to decreased capacity of brain to adaptive changes and increased vulnerability to neurotoxic damage. Brain-derived neurotrophic factor (BDNF) is a mediator involved in neuronal survival and plasticity of dopaminergic, cholinergic, and serotonergic neurons in the central nervous system (CNS). In this review, we summarize findings regarding altered BDNF in schizophrenia and depression and animal models, as well as the effects of antipsychotic and antidepressive treatments on the expression of BDNF.

Clinical application of neurotrophic factors: the potential for primary auditory neuron protection

PubMed Central

Gillespie, Lisa N.; Shepherd, Robert K.

2007-01-01

Sensorineural hearing loss, as a result of damage to or destruction of the sensory epithelia within the cochlea, is a common cause of deafness. The subsequent degeneration of the neural elements within the inner ear may impinge upon the efficacy of the cochlear implant. Experimental studies have demonstrated that neurotrophic factors can prevent this degeneration in animal models of deafness, and can even provide functional benefits. Neurotrophic factor therapy may, therefore, provide similar protective effects in humans, resulting in improved speech perception outcomes among cochlear implant patients. There are, however, numerous issues pertaining to delivery techniques and treatment regimes which need to be addressed prior to any clinical application. This review considers these issues in view of the potential therapeutic application of neurotrophic factors within the auditory system. PMID:16262651

Hyperbaric Oxygen Therapy Alleviates Carbon Monoxide Poisoning-Induced Delayed Memory Impairment by Preserving Brain-Derived Neurotrophic Factor-Dependent Hippocampal Neurogenesis.

PubMed

Liu, Wen-Chung; Yang, San-Nan; Wu, Chih-Wei J; Chen, Lee-Wei; Chan, Julie Y H

2016-01-01

To test the hypothesis that hyperbaric oxygen therapy ameliorates delayed cognitive impairment after acute carbon monoxide poisoning by promoting neurogenesis through upregulating the brain-derived neurotrophic factor in the hippocampus. Laboratory animal experiments. University/Medical center research laboratory. Adult, male Sprague-Dawley rats. Rats were divided into five groups: (1) non-carbon monoxide-treated control, (2) acute carbon monoxide poisoning, (3) acute carbon monoxide poisoning followed by 7-day hyperbaric oxygen treatment, (4) carbon monoxide + hyperbaric oxygen with additional intracerebroventricular infusion of Fc fragment of tyrosine kinase receptor B protein (TrkB-Fc) chimera, and (5) acute carbon monoxide poisoning followed by intracerebroventricular infusion of brain-derived neurotrophic factor. Acute carbon monoxide poisoning was achieved by exposing the rats to carbon monoxide at 2,500 ppm for 40 minutes, followed by 3,000 ppm for 20 minutes. Hyperbaric oxygen therapy (at 2.5 atmospheres absolute with 100% oxygen for 60 min) was conducted during the first 7 days after carbon monoxide poisoning. Recombinant human TrkB-Fc chimera or brain-derived neurotrophic factor was infused into the lateral ventricle via the implanted osmotic minipump. For labeling of mitotic cells in the hippocampus, bromodeoxyuridine was injected into the peritoneal cavity. Distribution of bromodeoxyuridine and two additional adult neurogenesis markers, Ki-67 and doublecortin, in the hippocampus was evaluated by immunohistochemistry or immunofluorescence staining. Tissue level of brain-derived neurotrophic factor was assessed by enzyme-linked immunosorbent assay. Cognitive behavior was evaluated by the use of eight-arm radial maze. Acute carbon monoxide poisoning significantly suppressed adult hippocampal neurogenesis evident by the reduction in number of bromodeoxyuridine-positive, Ki-67⁺, and doublecortin⁺ cells in the subgranular zone of the dentate gyrus. This suppression of adult neurogenesis by the carbon monoxide poisoning was appreciably alleviated by early treatment of hyperbaric oxygen. The hyperbaric oxygen treatment also promoted a sustained increase in hippocampal brain-derived neurotrophic factor level. Blockade of hippocampal brain-derived neurotrophic factor signaling with intracerebroventricular infusion of recombinant human TrkB-Fc chimera significantly blunted the protection by the hyperbaric oxygen on hippocampal neurogenesis; whereas intracerebroventricular infusion of brain-derived neurotrophic factor mimicked the action of hyperbaric oxygen and preserved hippocampal neurogenesis after acute carbon monoxide poisoning. Furthermore, acute carbon monoxide poisoning resulted in a delayed impairment of cognitive function. The hyperbaric oxygen treatment notably restored the cognitive impairment in a brain-derived neurotrophic factor-dependent manner. The early hyperbaric oxygen treatment may alleviate delayed memory impairment after acute carbon monoxide poisoning by preserving adult neurogenesis via an increase in hippocampal brain-derived neurotrophic factor content.

Brain-derived Neurotrophic Factor (BDNF) and gray matter volume in bipolar disorder.

PubMed

Poletti, S; Aggio, V; Hoogenboezem, T A; Ambrée, O; de Wit, H; Wijkhuijs, A J M; Locatelli, C; Colombo, C; Arolt, V; Drexhage, H A; Benedetti, F

2017-02-01

Bipolar Disorder (BD) is a severe psychiatric condition characterized by grey matter (GM) volumes reduction. Neurotrophic factors have been suggested to play a role in the neuroprogressive changes during the illness course. In particular peripheral brain-derived neurotrophic factor (BDNF) has been proposed as a potential biomarker related to disease activity and neuroprogression in BD. The aim of our study was to investigate if serum levels of BDNF are associated with GM volumes in BD patients and healthy controls (HC). We studied 36 inpatients affected by a major depressive episode in course of BD type I and 17 HC. Analysis of variance was performed to investigate the effect of diagnosis on GM volumes in the whole brain. Threshold for significance was P<0.05, Family Wise Error (FWE) corrected for multiple comparisons. All the analyses were controlled for the effect of nuisance covariates known to influence GM volumes, such as age, gender and lithium treatment. BD patients showed significantly higher serum BDNF levels compared with HC. Reduced GM volumes in BD patients compared to HC were observed in several brain areas, encompassing the caudate head, superior temporal gyrus, insula, fusiform gyrus, parahippocampal gyrus, and anterior cingulate cortex. The interaction analysis between BDNF levels and diagnosis showed a significant effect in the middle frontal gyrus. HC reported higher BDNF levels associated with higher GM volumes, whereas no association between BDNF and GM volumes was observed in BD. Our study seems to suggest that although the production of BDNF is increased in BD possibly to prevent and repair neural damage, its effects could be hampered by underlying neuroinflammatory processes interfering with the neurodevelopmental role of BDNF. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Infrequent detectable somatic mutations of the RET and glial cell line-derived neurotrophic factor (GDNF) genes in human pituitary adenomas.

PubMed

Yoshimoto, K; Tanaka, C; Moritani, M; Shimizu, E; Yamaoka, T; Yamada, S; Sano, T; Itakura, M

1999-02-01

RET is a receptor tyrosine kinase expressed in neuroendocrine cells and tumors. RET is activated by a ligand complex comprising glial cell line-derived neurotrophic factor (GDNF) and GDNF receptor-alpha (GDNFR-alpha). Activating mutations of the RET proto-oncogene were found in multiple endocrine neoplasia (MEN) 2 and in sporadic medullary thyroid carcinoma and pheochromocytoma of neuroendocrine origin. Mutations of the RET proto-oncogene and the glial cell line-derived neurotrophic factor (GDNF) gene were examined in human pituitary tumors. No mutations of the RET proto-oncogene including the cysteine-rich region or codon 768 and 918 in the tyrosine kinase domain were detected in 172 human pituitary adenomas either by polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) or by PCR-restriction fragment length polymorphism (RFLP). Further, somatic mutations of the GDNF gene in 33 human pituitary adenomas were not detected by PCR-SSCP. One polymorphism of the GDNF gene at codon 145 of TGC or TGT was observed in a prolactinoma. The RET proto-oncogene message was detected in a normal human pituitary gland or 4 of 4 human pituitary adenomas with reverse transcription (RT)-PCR, and in rodent pituitary tumor cell lines with Western blotting. The expression of GDNF gene was detected in 1 of 4 human somatotroph adenomas, 1 of 2 corticotroph adenomas, and 2 of 6 rodent pituitary tumor cell lines with RT-PCR. Based on these, it is concluded that somatic mutations of the RET proto-oncogene or the GDNF gene do not appear to play a major role in the pituitary tumorigenesis in examined tumors.

Fluoxetine ameliorates behavioral and neuropathological deficits in a transgenic model mouse of α-synucleinopathy.

PubMed

Ubhi, Kiren; Inglis, Chandra; Mante, Michael; Patrick, Christina; Adame, Anthony; Spencer, Brian; Rockenstein, Edward; May, Verena; Winkler, Juergen; Masliah, Eliezer

2012-04-01

The term α-synucleinopathies refers to a group of age-related neurological disorders including Parkinson's disease (PD), Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA) that display an abnormal accumulation of alpha-synuclein (α-syn). In contrast to the neuronal α-syn accumulation observed in PD and DLB, MSA is characterized by a widespread oligodendrocytic α-syn accumulation. Transgenic mice expressing human α-syn under the oligodendrocyte-specific myelin basic protein promoter (MBP1-hαsyn tg mice) model many of the behavioral and neuropathological alterations observed in MSA. Fluoxetine, a selective serotonin reuptake inhibitor, has been shown to be protective in toxin-induced models of PD, however its effects in an in vivo transgenic model of α-synucleinopathy remain unclear. In this context, this study examined the effect of fluoxetine in the MBP1-hαsyn tg mice, a model of MSA. Fluoxetine administration ameliorated motor deficits in the MBP1-hαsyn tg mice, with a concomitant decrease in neurodegenerative pathology in the basal ganglia, neocortex and hippocampus. Fluoxetine administration also increased levels of the neurotrophic factors, GDNF (glial-derived neurotrophic factor) and BDNF (brain-derived neurotrophic factor) in the MBP1-hαsyn tg mice compared to vehicle-treated tg mice. This fluoxetine-induced increase in GDNF and BDNF protein levels was accompanied by activation of the ERK signaling pathway. The effects of fluoxetine administration on myelin and serotonin markers were also examined. Collectively these results indicate that fluoxetine may represent a novel therapeutic intervention for MSA and other neurodegenerative disorders. Copyright © 2011 Elsevier Inc. All rights reserved.

Role of the autonomic nervous system in tumorigenesis and metastasis

PubMed Central

Magnon, Claire

2015-01-01

Convergence of multiple stromal cell types is required to develop a tumorigenic niche that nurtures the initial development of cancer and its dissemination. Although the immune and vascular systems have been shown to have strong influences on cancer, a growing body of evidence points to a role of the nervous system in promoting cancer development. This review discusses past and current research that shows the intriguing role of autonomic nerves, aided by neurotrophic growth factors and axon cues, in creating a favorable environment for the promotion of tumor formation and metastasis. PMID:27308436

Role of the autonomic nervous system in tumorigenesis and metastasis.

PubMed

Magnon, Claire

2015-01-01

Convergence of multiple stromal cell types is required to develop a tumorigenic niche that nurtures the initial development of cancer and its dissemination. Although the immune and vascular systems have been shown to have strong influences on cancer, a growing body of evidence points to a role of the nervous system in promoting cancer development. This review discusses past and current research that shows the intriguing role of autonomic nerves, aided by neurotrophic growth factors and axon cues, in creating a favorable environment for the promotion of tumor formation and metastasis.

Teaching High School Biology Students to Coordinate Text and Diagrams: Relations with Transfer, Effort, and Spatial Skill

ERIC Educational Resources Information Center

Bergey, Bradley W.; Cromley, Jennifer G.; Newcombe, Nora S.

2015-01-01

There is growing evidence that targeted instruction can improve diagram comprehension, yet one of the skills identified in the diagram comprehension literature--coordinating multiple representations--has rarely been directly taught to students and tested as a classroom intervention. We created a Coordinating Multiple Representation (CMR)…

Coordinating Multiple Representations in a Reform Calculus Textbook

ERIC Educational Resources Information Center

Chang, Briana L.; Cromley, Jennifer G.; Tran, Nhi

2015-01-01

Coordination of multiple representations (CMR) is widely recognized as a critical skill in mathematics and is frequently demanded in reform calculus textbooks. However, little is known about the prevalence of coordination tasks in such textbooks. We coded 707 instances of CMR in a widely used reform calculus textbook and analyzed the distributions…

Coordinating Multiple Representations in a Reform Calculus Textbook

ERIC Educational Resources Information Center

Chang, Briana L.; Cromley, Jennifer G.; Tran, Nhi

2016-01-01

Coordination of multiple representations (CMR) is widely recognized as a critical skill in mathematics and is frequently demanded in reform calculus textbooks. However, little is known about the prevalence of coordination tasks in such textbooks. We coded 707 instances of CMR in a widely used reform calculus textbook and analyzed the distributions…

Evidence that DmMANF is an invertebrate neurotrophic factor supporting dopaminergic neurons

PubMed Central

Palgi, Mari; Lindström, Riitta; Peränen, Johan; Piepponen, T. Petteri; Saarma, Mart; Heino, Tapio I.

2009-01-01

In vertebrates the development and function of the nervous system is regulated by neurotrophic factors (NTFs). Despite extensive searches no neurotrophic factors have been found in invertebrates. However, cell ablation studies in Drosophila suggest trophic interaction between neurons and glia. Here we report the invertebrate neurotrophic factor in Drosophila, DmMANF, homologous to mammalian MANF and CDNF. DmMANF is expressed in glia and essential for maintenance of dopamine positive neurites and dopamine levels. The abolishment of both maternal and zygotic DmMANF leads to the degeneration of axonal bundles in the embryonic central nervous system and subsequent nonapoptotic cell death. The rescue experiments confirm DmMANF as a functional ortholog of the human MANF gene thus opening the window for comparative studies of this protein family with potential for the treatment of Parkinson's disease. PMID:19164766

Mechanisms of extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor signal transduction pathway in depressive disorder☆

PubMed Central

Wang, Hongyan; Zhang, Yingquan; Qiao, Mingqi

2013-01-01

The extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor signal transduction pathway plays an important role in the mechanism of action of antidepressant drugs and has dominated recent studies on the pathogenesis of depression. In the present review we summarize the known roles of extracellular signal-regulated kinase, cAMP response element-binding protein and brain-derived neurotrophic factor in the pathogenesis of depression and in the mechanism of action of antidepressant medicines. The extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor pathway has potential to be used as a biological index to help diagnose depression, and as such it is considered as an important new target in the treatment of depression. PMID:25206732

Role of Neurotrophins in the Development and Function of Neural Circuits that Regulate Energy Homeostasis

PubMed Central

Fargali, Samira; Sadahiro, Masato; Jiang, Cheng; Frick, Amy L.; Indall, Tricia; Cogliani, Valeria; Welagen, Jelle; Lin, Wei-jye; Salton, Stephen R.

2012-01-01

Members of the neurotrophin family, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5), and other neurotrophic growth factors such as ciliary neurotrophic factor (CNTF) and artemin, regulate peripheral and central nervous system development and function. A subset of the neurotrophin-dependent pathways in the hypothalamus, brainstem, and spinal cord, and those that project via the sympathetic nervous system to peripheral metabolic tissues including brown and white adipose tissue (BAT and WAT), muscle and liver, regulate feeding, energy storage, and energy expenditure. We briefly review the role that neurotrophic growth factors play in energy balance, as regulators of neuronal survival and differentiation, neurogenesis, and circuit formation and function, and as inducers of critical gene products that control energy homeostasis. PMID:22581449

Neurotrophic keratitis after transscleral diode laser cyclophotocoagulation.

PubMed

Fernández-Vega González, Á; Barraquer Compte, R I; Cárcamo Martínez, A L; Torrico Delgadillo, M; de la Paz, M F

2016-07-01

To study the relationship between treatment with diode laser transscleral cyclophotocoagulation and development a neurotrophic keratitis due to the damage of the sensitive corneal innervation. A study was conducted on 5 eyes of 5 patients who were treated with diode laser transscleral cyclophotocoagulation and soon developed neurotrophic ulcers. Personal characteristics of the patients were collected, as well as refraction and risk factors for corneal hypoesthesia, and the parameters of the laser used in the surgery. It was found that the 5 patients had predisposing factors of corneal hypoesthesia prior to surgery (chronic use of topical beta blockers, surgery with corneal incisions, diabetes mellitus, or corneal dystrophies); however none had developed neurotrophic keratitis until the cyclophotocoagulation was performed. It also showed that 4 of them were highly myopic, and they all were treated with high laser parameters (with an average of 2880 mW for 3s at an average surface of 275°), triggering neurotrophic ulcers between 10 and 35 days after surgery. Neurotrophic keratitis is a rare complication that can occur after diode laser transscleral cyclophotocoagulation, secondary to the damage of the long ciliary nerves. The emergence of this disorder can be triggered by the existence of previous risk factors, including high myopia, thus it is important to respect the recommended treatment parameters to prevent the development of this disorder. Copyright © 2015 Sociedad Española de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.

Brain-derived neurotrophic factor mediates cognitive improvements following acute exercise.

PubMed

Borror, Andrew

2017-09-01

The mechanisms causing improved cognition following acute exercise are poorly understood. This article proposes that brain-derived neurotrophic factor (BDNF) is the main factor contributing to improved cognition following exercise. Additionally, it argues that cerebral blood flow (CBF) and oxidative stress explain the release of BDNF from cerebral endothelial cells. One way to test these hypotheses is to block endothelial function and measure the effect on BDNF levels and cognitive performance. The CBF and oxidative stress can also be examined in relationship to BDNF using a multiple linear regression. If these hypotheses are true, there would be a linear relationship between CBF+oxidative stress and BDNF levels as well as between BDNF levels and cognitive performance. The novelty of these hypotheses comes from the emphasis on the cerebral endothelium and the interplay between BDNF, CBF, and oxidative stress. If found to be valid, these hypotheses would draw attention to the cerebral endothelium and provide direction for future research regarding methods to optimize BDNF release and enhance cognition. Elucidating these mechanisms would provide direction for expediting recovery in clinical populations, such as stroke, and maintaining quality of life in the elderly. Copyright © 2017 Elsevier Ltd. All rights reserved.

Neural Plasticity and Proliferation in the Generation of Antidepressant Effects: Hippocampal Implication

PubMed Central

Pilar-Cuéllar, Fuencisla; Vidal, Rebeca; Díaz, Alvaro; Castro, Elena; dos Anjos, Severiano; Pascual-Brazo, Jesús; Linge, Raquel; Vargas, Veronica; Blanco, Helena; Martínez-Villayandre, Beatriz; Pazos, Ángel; Valdizán, Elsa M.

2013-01-01

It is widely accepted that changes underlying depression and antidepressant-like effects involve not only alterations in the levels of neurotransmitters as monoamines and their receptors in the brain, but also structural and functional changes far beyond. During the last two decades, emerging theories are providing new explanations about the neurobiology of depression and the mechanism of action of antidepressant strategies based on cellular changes at the CNS level. The neurotrophic/plasticity hypothesis of depression, proposed more than a decade ago, is now supported by multiple basic and clinical studies focused on the role of intracellular-signalling cascades that govern neural proliferation and plasticity. Herein, we review the state-of-the-art of the changes in these signalling pathways which appear to underlie both depressive disorders and antidepressant actions. We will especially focus on the hippocampal cellularity and plasticity modulation by serotonin, trophic factors as brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF) through intracellular signalling pathways—cAMP, Wnt/β-catenin, and mTOR. Connecting the classic monoaminergic hypothesis with proliferation/neuroplasticity-related evidence is an appealing and comprehensive attempt for improving our knowledge about the neurobiological events leading to depression and associated to antidepressant therapies. PMID:23862076

Serum brain-derived neurotrophic factor levels and personality traits in patients with major depression.

PubMed

Nomoto, Hiroshi; Baba, Hajime; Satomura, Emi; Maeshima, Hitoshi; Takebayashi, Naoko; Namekawa, Yuki; Suzuki, Toshihito; Arai, Heii

2015-03-04

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors. Previous studies have demonstrated lower serum BDNF levels in patients with major depressive disorder (MDD) and reported an association between BDNF levels and depression-related personality traits in healthy subjects. The aim of the present study was to explore for a possible association between peripheral BDNF levels and personality traits in patients with MDD. In this cross-sectional study, a total of 123 inpatients with MDD (Diagnostic and Statistical Manual for Mental Disorders, 4th edition) at the Juntendo University Koshigaya Hospital were recruited. Serum levels of BDNF were measured. Personality traits were assessed using the 125-item short version of the Temperament and Character Inventory (TCI). Multiple regression analysis adjusted for age, sex, body mass index, dose of antidepressant, and depression severity showed that TCI Self-Directedness (SD) scores were negatively associated with serum BDNF levels (β = -0.23, p = 0.026). MDD patients who have low SD did not show the reduction in serum BDNF levels that is normally associated with depressive state. Our findings suggest that depression-related biological changes may not occur in these individuals.

Early maternal separation followed by later stressors leads to dysregulation of the HPA-axis and increases in hippocampal NGF and NT-3 levels in a rat model.

PubMed

Faure, Jacqueline; Uys, Joachim D K; Marais, Lelanie; Stein, Dan J; Daniels, Willie M U

2006-09-01

Early adverse life events, followed by subsequent stressors, appear to increase susceptibility for subsequent onset of psychiatric disorders in humans. The molecular mechanisms that underlie this phenomenon remain unclear, but dysregulation of the HPA axis and alterations in neurotrophic factors have been implicated. The present study investigated the effects in rodents of early maternal separation, followed by stress in adolescence and adulthood on later HPA-axis activity and hippocampal neurotrophin levels (brain-derived neurotrophic factor, nerve growth factor, and neurotrophin-3). Animals subjected to repeated stressors showed a significant decrease in basal ACTH (p < 0.05) and CORT (p < 0.05) levels when compared to controls, as well as significantly increased levels of NGF in the dorsal (p < 0.001) and ventral hippocampus (p < 0.01), and of NT-3 in the dorsal hippocampus (p < 0.01). Dysregulation of the HPA axis after multiple stressors is consistent with previous preclinical and clinical work. Given that neurotrophins are important in neuronal survival and plasticity, it is possible to speculate that their elevation reflects a compensatory mechanism.

Comparison of plasma pigment epithelium-derived factor (PEDF), retinol binding protein 4 (RBP-4), chitinase-3-like protein 1 (YKL-40) and brain-derived neurotrophic factor (BDNF) for the identification of insulin resistance.

PubMed

Toloza, F J K; Pérez-Matos, M C; Ricardo-Silgado, M L; Morales-Álvarez, M C; Mantilla-Rivas, J O; Pinzón-Cortés, J A; Pérez-Mayorga, M; Arévalo-García, M L; Tolosa-González, G; Mendivil, C O

2017-09-01

To evaluate and compare the association of four potential insulin resistance (IR) biomarkers (pigment-epithelium-derived factor [PEDF], retinol-binding-protein-4 [RBP-4], chitinase-3-like protein 1 [YKL-40] and brain-derived neurotrophic factor [BDNF]) with objective measures of IR. We studied 81 subjects with different metabolic profiles. All participants underwent a 5-point OGTT with calculation of multiple IR indexes. A subgroup of 21 participants additionally underwent a hyperinsulinemic-euglycemic clamp. IR was defined as belonging to the highest quartile of incremental area under the insulin curve (iAUCins), or to the lowest quartile of the insulin sensitivity index (ISI). PEDF was associated with adiposity variables. PEDF and RBP4 increased linearly across quartiles of iAUCins (for PEDF p-trend=0.029; for RBP-4 p-trend=0.053). YKL-40 and BDNF were not associated with any adiposity or IR variable. PEDF and RBP-4 levels identified individuals with IR by the iAUCins definition: A PEDF cutoff of 11.9ng/mL had 60% sensitivity and 68% specificity, while a RBP-4 cutoff of 71.6ng/mL had 70% sensitivity and 57% specificity. In multiple regression analyses simultaneously including clinical variables and the studied biomarkers, only BMI, PEDF and RBP-4 remained significant predictors of IR. Plasma PEDF and RBP4 identified IR in subjects with no prior diagnosis of diabetes. Copyright © 2017 Elsevier Inc. All rights reserved.

Amitriptyline induces brain-derived neurotrophic factor (BDNF) mRNA expression through ERK-dependent modulation of multiple BDNF mRNA variants in primary cultured rat cortical astrocytes and microglia.

PubMed

Hisaoka-Nakashima, Kazue; Kajitani, Naoto; Kaneko, Masahiro; Shigetou, Takahiro; Kasai, Miho; Matsumoto, Chie; Yokoe, Toshiki; Azuma, Honami; Takebayashi, Minoru; Morioka, Norimitsu; Nakata, Yoshihiro

2016-03-01

A significant role of brain-derived neurotrophic factor (BDNF) has been previously implicated in the therapeutic effect of antidepressants. To ascertain the contribution of specific cell types in the brain that produce BDNF following antidepressant treatment, the effects of the tricyclic antidepressant amitriptyline on rat primary neuronal, astrocytic and microglial cortical cultures were examined. Amitriptyline increased the expression of BDNF mRNA in astrocytic and microglial cultures but not neuronal cultures. Antidepressants with distinct mechanisms of action, such as clomipramine, duloxetine and fluvoxamine, also increased BDNF mRNA expression in astrocytic and microglial cultures. There are multiple BDNF mRNA variants (exon I, IIA, IV and VI) expressed in astrocytes and microglia and the variant induced by antidepressants has yet to be elaborated. Treatment with antidepressants increased the expression of exon I, IV and VI in astrocyte and microglia. Clomipramine alone significantly upregulated expression of exon IIA. The amitriptyline-induced expression of both total and individual BDNF mRNA variants (exon I, IV and VI) were blocked by MEK inhibitor U0126, indicating MEK/ERK signaling is required in the expression of BDNF. These findings indicate that non-neural cells are a significant target of antidepressants and further support the contention that glial production of BDNF is crucial role in the therapeutic effect of antidepressants. The current data suggest that targeting of glial function could lead to the development of antidepressants with a truly novel mechanism of action. Copyright © 2016 Elsevier B.V. All rights reserved.

The role of dorsal root ganglia activation and brain-derived neurotrophic factor in multiple sclerosis

PubMed Central

Zhu, Wenjun; Frost, Emma E; Begum, Farhana; Vora, Parvez; Au, Kelvin; Gong, Yuewen; MacNeil, Brian; Pillai, Prakash; Namaka, Mike

2012-01-01

Abstract Multiple sclerosis (MS) is characterized by focal destruction of the white matter of the brain and spinal cord. The exact mechanisms underlying the pathophysiology of the disease are unknown. Many studies have shown that MS is predominantly an autoimmune disease with an inflammatory phase followed by a demyelinating phase. Recent studies alongside current treatment strategies, including glatiramer acetate, have revealed a potential role for brain-derived neurotrophic factor (BDNF) in MS. However, the exact role of BDNF is not fully understood. We used the experimental autoimmune encephalomyelitis (EAE) model of MS in adolescent female Lewis rats to identify the role of BDNF in disease progression. Dorsal root ganglia (DRG) and spinal cords were harvested for protein and gene expression analysis every 3 days post-disease induction (pdi) up to 15 days. We show significant increases in BDNF protein and gene expression in the DRG of EAE animals at 12 dpi, which correlates with peak neurological disability. BDNF protein expression in the spinal cord was significantly increased at 12 dpi, and maintained at 15 dpi. However, there was no significant change in mRNA levels. We show evidence for the anterograde transport of BDNF protein from the DRG to the dorsal horn of the spinal cord via the dorsal roots. Increased levels of BDNF within the DRG and spinal cord in EAE may facilitate myelin repair and neuroprotection in the CNS. The anterograde transport of DRG-derived BDNF to the spinal cord may have potential implications in facilitating central myelin repair and neuroprotection. PMID:22050733

Effects of Exercise on Progranulin Levels and Gliosis in Progranulin-Insufficient Mice.

PubMed

Arrant, Andrew E; Patel, Aashka R; Roberson, Erik D

2015-01-01

Loss-of-function mutations in progranulin ( GRN ) are one of the most common genetic causes of frontotemporal dementia (FTD), a progressive, fatal neurodegenerative disorder with no available disease-modifying treatments. Through haploinsufficiency, these mutations reduce levels of progranulin, a protein that has neurotrophic and anti-inflammatory effects. Increasing progranulin expression from the intact allele is therefore a potential approach for treating individuals with GRN mutations. Based on the well-known effects of physical exercise on other neurotrophic factors, we hypothesized that exercise might increase brain progranulin levels. We tested this hypothesis in progranulin heterozygous ( Grn + / - ) mice, which model progranulin haploinsufficiency. We housed wild-type and progranulin-insufficient mice in standard cages or cages with exercise wheels for 4 or 7.5 weeks, and then measured brain and plasma progranulin levels. Although exercise modestly increased progranulin in very young (2-month-old) wild-type mice, this effect was limited to the hippocampus. Exercise did not increase brain progranulin mRNA or protein in multiple regions, nor did it increase plasma progranulin, in 4- to 8-month-old wild-type or Grn + / - mice, across multiple experiments and under conditions that increased hippocampal BDNF and neurogenesis. Grn - / - mice were included in the study to test for progranulin-independent benefits of exercise on gliosis. Exercise attenuated cortical microgliosis in 8-month-old Grn - / - mice, consistent with a progranulin-independent, anti-inflammatory effect of exercise. These results suggest that exercise may have some modest, nonspecific benefits for FTD patients with progranulin mutations, but do not support exercise as a strategy to raise progranulin levels.

3-hydroxymorphinan is neurotrophic to dopaminergic neurons and is also neuroprotective against LPS-induced neurotoxicity.

PubMed

Zhang, Wei; Qin, Liya; Wang, Tongguang; Wei, Sung-Jen; Gao, Hui-ming; Liu, Jie; Wilson, Belinda; Liu, Bin; Zhang, Wanqin; Kim, Hyoung-Chun; Hong, Jau-Shyong

2005-03-01

The purpose of this study was to develop a novel therapy for Parkinson's disease (PD). We recently reported that dextromethorphan (DM), an active ingredient in a variety of widely used anticough remedies, protected dopaminergic neurons in rat primary mesencephalic neuron-glia cultures against lipopolysaccharide (LPS)-mediated degeneration and provided potent protection for dopaminergic neurons in a MPTP mouse model. The underlying mechanism for the protective effect of DM was attributed to its anti-inflammatory activity through inhibition of microglia activation. In an effort to develop more potent compounds for the treatment of PD, we have screened a series of analogs of DM, and 3-hydroxymorphinan (3-HM) emerged as a promising candidate for this purpose. Our study using primary mesencephalic neuron-glia cultures showed that 3-HM provided more potent neuroprotection against LPS-induced dopaminergic neurotoxicity than its parent compound. The higher potency of 3-HM was attributed to its neurotrophic effect in addition to the anti-inflammatory effect shared by both DM and 3-HM. First, we showed that 3-HM exerted potent neuroprotective and neurotrophic effects on dopaminergic neurons in rat primary mesencephalic neuron-glia cultures treated with LPS. The neurotrophic effect of 3-HM was glia-dependent since 3-HM failed to show any protective effect in the neuron-enriched cultures. We subsequently demonstrated that it was the astroglia, not the microglia, that contributed to the neurotrophic effect of 3-HM. This conclusion was based on the reconstitution studies, in which we added different percentages of microglia (10-20%) or astroglia (40-50%) back to the neuron-enriched cultures and found that 3-HM was neurotrophic after the addition of astroglia, but not microglia. Furthermore, 3-HM-treated astroglia-derived conditioned media exerted a significant neurotrophic effect on dopaminergic neurons. It appeared likely that 3-HM caused the release of neurotrophic factor(s) from astroglia, which in turn was responsible for the neurotrophic effect. Second, the anti-inflammatory mechanism was also important for the neuroprotective activity of 3-HM because the more microglia were added back to the neuron-enriched cultures, the more significant neuroprotective effect was observed. The anti-inflammatory mechanism of 3-HM was attributed to its inhibition of LPS-induced production of an array of pro-inflammatory and neurotoxic factors, including nitric oxide (NO), tumor necrosis factor alpha (TNF-alpha), prostaglandin E2 (PGE2) and reactive oxygen species (ROS). In conclusion, this study showed that 3-HM exerted potent neuroprotection by acting on two different targets: a neurotrophic effect mediated by astroglia and an anti-inflammatory effect mediated by the inhibition of microglial activation. 3-HM thus possesses these two important features necessary for an effective neuroprotective agent. In view of the well-documented very low toxicity of DM and its analogs, this report may provide an important new direction for the development of therapeutic interventions for inflammation-related diseases such as PD.

Neurotrophic factors and receptors in the immature and adult spinal cord after mechanical injury or kainic acid.

PubMed

Widenfalk, J; Lundströmer, K; Jubran, M; Brene, S; Olson, L

2001-05-15

Delivery of neurotrophic factors to the injured spinal cord has been shown to stimulate neuronal survival and regeneration. This indicates that a lack of sufficient trophic support is one factor contributing to the absence of spontaneous regeneration in the mammalian spinal cord. Regulation of the expression of neurotrophic factors and receptors after spinal cord injury has not been studied in detail. We investigated levels of mRNA-encoding neurotrophins, glial cell line-derived neurotrophic factor (GDNF) family members and related receptors, ciliary neurotrophic factor (CNTF), and c-fos in normal and injured spinal cord. Injuries in adult rats included weight-drop, transection, and excitotoxic kainic acid delivery; in newborn rats, partial transection was performed. The regulation of expression patterns in the adult spinal cord was compared with that in the PNS and the neonate spinal cord. After mechanical injury of the adult rat spinal cord, upregulations of NGF and GDNF mRNA occurred in meningeal cells adjacent to the lesion. BDNF and p75 mRNA increased in neurons, GDNF mRNA increased in astrocytes close to the lesion, and GFRalpha-1 and truncated TrkB mRNA increased in astrocytes of degenerating white matter. The relatively limited upregulation of neurotrophic factors in the spinal cord contrasted with the response of affected nerve roots, in which marked increases of NGF and GDNF mRNA levels were observed in Schwann cells. The difference between the ability of the PNS and CNS to provide trophic support correlates with their different abilities to regenerate. Kainic acid delivery led to only weak upregulations of BDNF and CNTF mRNA. Compared with several brain regions, the overall response of the spinal cord tissue to kainic acid was weak. The relative sparseness of upregulations of endogenous neurotrophic factors after injury strengthens the hypothesis that lack of regeneration in the spinal cord is attributable at least partly to lack of trophic support.

SKF83959 Produces Antidepressant Effects in a Chronic Social Defeat Stress Model of Depression through BDNF-TrkB Pathway

PubMed Central

Jiang, Bo; Wang, Fang; Yang, Si; Fang, Peng; Deng, Zhi-Fang; Xiao, Jun-Li; Hu, Zhuang-Li

2015-01-01

Background: SKF83959 stimulates the phospholipase Cβ/inositol phosphate 3 pathway, resulting in the activation of Ca2+/calmodulin-dependent kinase IIα, which affects the synthesis of brain-derived neurotrophic factor, a neurotrophic factor critical for the pathophysiology of depression. Previous reports showed that SKF83959 elicited antidepressant activity in the forced swim test and tail suspension test as a novel triple reuptake inhibitor. However, there are no studies showing the effects of SKF83959 in a chronic stress model of depression and the role of phospholipase C/inositol phosphate 3/calmodulin-dependent kinase IIα/brain-derived neurotrophic factor pathway in SKF83959-mediated antidepressant effects. Methods: In this study, SKF83959 was firstly investigated in the chronic social defeat stress model of depression. The changes in hippocampal neurogenesis, dendrite spine density, and brain-derived neurotrophic factor signaling pathway after chronic social defeat stress and SKF83959 treatment were then investigated. Pharmacological inhibitors and small interfering RNA/short hairpin RNA methods were further used to explore the antidepressive mechanisms of SKF83959. Results: We found that SKF83959 produced antidepressant effects in the chronic social defeat stress model and also restored the chronic social defeat stress-induced decrease in hippocampal brain-derived neurotrophic factor signaling pathway, dendritic spine density, and neurogenesis. By using various inhibitors and siRNA/shRNA methods, we further demonstrated that the hippocampal dopamine D5 receptor, phospholipase C/inositol phosphate 3/ calmodulin-dependent kinase IIα pathway, and brain-derived neurotrophic factor system are all necessary for the SKF83959 effects. Conclusion: These results suggest that SKF83959 can be developed as a novel antidepressant and produces antidepressant effects via the hippocampal D5/ phospholipase C/inositol phosphate 3/calmodulin-dependent kinase IIα/brain-derived neurotrophic factor pathway. PMID:25522427

Actions of Brain-Derived Neurotrophic Factor and Glucocorticoid Stress in Neurogenesis

PubMed Central

Numakawa, Tadahiro; Odaka, Haruki; Adachi, Naoki

2017-01-01

Altered neurogenesis is suggested to be involved in the onset of brain diseases, including mental disorders and neurodegenerative diseases. Neurotrophic factors are well known for their positive effects on the proliferation/differentiation of both embryonic and adult neural stem/progenitor cells (NSCs/NPCs). Especially, brain-derived neurotrophic factor (BDNF) has been extensively investigated because of its roles in the differentiation/maturation of NSCs/NPCs. On the other hand, recent evidence indicates a negative impact of the stress hormone glucocorticoids (GCs) on the cell fate of NSCs/NPCs, which is also related to the pathophysiology of brain diseases, such as depression and autism spectrum disorder. Furthermore, studies including ours have demonstrated functional interactions between neurotrophic factors and GCs in neural events, including neurogenesis. In this review, we show and discuss relationships among the behaviors of NSCs/NPCs, BDNF, and GCs. PMID:29099059

Differential stimulation of neurotrophin release by the biocompatible nano-material (carbon nanotube) in primary cultured neurons.

PubMed

Kim, Yun Gi; Kim, Jong Wan; Pyeon, Hee Jang; Hyun, Jung Keun; Hwang, Ji-Young; Choi, Seong-Jun; Lee, Ja-Yeon; Deák, Ferenc; Kim, Hae-Won; Lee, Young Il

2014-01-01

In order to develop novel, effective therapies for central nervous system regeneration, it is essential to better understand the role of neurotrophic factors and to design, accordingly, better artificial scaffolds to support both neurite outgrowth and synapse formation. Both nerve growth factor and brain-derived neurotrophic factor are major factors in neural survival, development, synaptogenesis, and synaptic connectivity of primary cultured neurons. As a prime candidate coating material for such neural cultures, carbon nanotubes offer unique structural, mechanical, and electrical properties. In this study, carbon nanotubes coated glass-coverslips were used as the matrix of a primary neural culture system used to investigate the effects of carbon nanotubes on neurite outgrowth and nerve growth factor/brain-derived neurotrophic factor release and expression. For these purposes, we performed comparative analyses of primary cultured neurons on carbon nanotubes coated, non-coated, and Matrigel-coated coverslips. The morphological findings showed definite carbon nanotubes effects on the neurite outgrowths and synaptogenic figures in both cortical and hippocampal neurons when compared with the non-coated negative control. Although the carbon nanotubes did not change neurotrophin expression levels, it stimulated brain-derived neurotrophic factor release into the media from both types of neurons. Accordingly, we suggest a different mechanism of action between carbon nanotubes and Matrigel in relation to the specific neurotrophic factors. Since carbon nanotubes supply long-term extracellular molecular cues for the survival and neurite outgrowths of cultured neurons, the results from this study will contribute to an understanding of carbon nanotubes biological effects and provide new insight into their role in the secretion of neurotrophic factors.

Role of Neurotrophic Factors in Parkinson's Disease.

PubMed

Tome, Diogo; Fonseca, Carla Pais; Campos, Filipa Lopes; Baltazar, Graca

2017-01-01

Parkinson's disease is an age-associated progressive neurodegenerative disorder that has gained crescent social and economic impact due to the aging of the western society. All current therapies are symptomatic and fail to reverse or halt the progression of dopaminergic neurons loss. The discovery of the capability of neurotrophic factors to protect these neurons lead numerous research groups to focus their efforts in developing therapies aiming at promoting the control of Parkinson´s disease through the delivery of neurotrophic factors to the brain or by boosting their endogenous levels. Both strategies were successful in inducing protection of dopaminergic neurons and motor recovery in preclinical models of the disease. Contrariwise, very limited success was obtained in clinical studies, where glial cell line-derived neurotrophic factor and neurturin were the neurotrophic factors of choice for Parkinson's disease therapy. These drawbacks motivate the development of novel forms of delivery or the modification of the injected molecules aiming at providing a more stable and effective administration with improved diffusion in the target tissue, and without the immune responses observed in the earliest clinical studies. Although promising results were obtained with some of these new approaches performed in experimental models of the disease, they were not yet tested in human studies. In this review, we present the current knowledge on neurotrophic factors and their role in Parkinson's disease, focusing on the strategies that have been developed to increase their levels in target areas of the brain to achieve protection of dopaminergic neurons and motor behaviour recovery. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Coordinating Multiple Spacecraft Assets for Joint Science Campaigns

NASA Technical Reports Server (NTRS)

Estlin, Tara; Chien, Steve; Castano, Rebecca; Gaines, Daniel; de Granville, Charles; Doubleday, Josh; Anderson, Robert C.; Knight, Russell; Bornstein, Benjamin; Rabideau, Gregg;

DREAM mediates cAMP-dependent, Ca2+-induced stimulation of GFAP gene expression and regulates cortical astrogliogenesis.

PubMed

Cebolla, Beatriz; Fernández-Pérez, Antonio; Perea, Gertrudis; Araque, Alfonso; Vallejo, Mario

2008-06-25

In the developing mouse brain, once the generation of neurons is mostly completed during the prenatal period, precisely coordinated signals act on competent neural precursors to direct their differentiation into astrocytes, which occurs mostly after birth. Among these signals, those provided by neurotrophic cytokines and bone morphogenetic proteins appear to have a key role in triggering the neurogenic to gliogenic switch and in regulating astrocyte numbers. In addition, we have reported previously that the neurotrophic peptide pituitary adenylate cyclase-activating polypeptide (PACAP) is able to promote astrocyte differentiation of cortical precursors via activation of a cAMP-dependent pathway. Signals acting on progenitor cells of the developing cortex to generate astrocytes activate glial fibrillary acidic protein (GFAP) gene expression, but the transcriptional mechanisms that regulate this activation are unclear. Here, we identify the previously known transcriptional repressor downstream regulatory element antagonist modulator (DREAM) as an activator of GFAP gene expression. We found that DREAM occupies specific sites on the GFAP promoter before and after differentiation is initiated by exposure of cortical progenitor cells to PACAP. PACAP raises intracellular calcium concentration via a mechanism that requires cAMP, and DREAM-mediated transactivation of the GFAP gene requires the integrity of calcium-binding domains. Cortical progenitor cells from dream(-/-) mice fail to express GFAP in response to PACAP. Moreover, the neonatal cortex of dream(-/-) mice exhibits a reduced number of astrocytes and increased number of neurons. These results identify the PACAP-cAMP-Ca(2+)-DREAM cascade as a new pathway to activate GFAP gene expression during astrocyte differentiation.

Activation of signaling pathways following localized delivery of systemically administered neurotrophic factors across the blood-brain barrier using focused ultrasound and microbubbles

NASA Astrophysics Data System (ADS)

Baseri, Babak; Choi, James J.; Deffieux, Thomas; Samiotaki, Gesthimani; Tung, Yao-Sheng; Olumolade, Oluyemi; Small, Scott A.; Morrison, Barclay, III; Konofagou, Elisa E.

2012-04-01

The brain-derived neurotrophic factor (BDNF) has been shown to have broad neuroprotective effects in addition to its therapeutic role in neurodegenerative disease. In this study, the efficacy of delivering exogenous BDNF to the left hippocampus is demonstrated in wild-type mice (n = 7) through the noninvasively disrupted blood-brain barrier (BBB) using focused ultrasound (FUS). The BDNF bioactivity was found to be preserved following delivery as assessed quantitatively by immunohistochemical detection of the pTrkB receptor and activated pAkt, pMAPK, and pCREB in the hippocampal neurons. It was therefore shown for the first time that systemically administered neurotrophic factors can cross the noninvasively disrupted BBB and trigger neuronal downstream signaling effects in a highly localized region in the brain. This is the first time that the administered molecule is tracked through the BBB and localized in the neuron triggering molecular effects. Additional preliminary findings are shown in wild-type mice with two additional neurotrophic factors such as the glia-derived neurotrophic factor (n = 12) and neurturin (n = 2). This further demonstrates the impact of FUS for the early treatment of CNS diseases at the cellular and molecular level and strengthens its premise for FUS-assisted drug delivery and efficacy.

An Architecture for Controlling Multiple Robots

NASA Technical Reports Server (NTRS)

Aghazarian, Hrand; Pirjanian, Paolo; Schenker, Paul; Huntsberger, Terrance

2004-01-01

The Control Architecture for Multirobot Outpost (CAMPOUT) is a distributed-control architecture for coordinating the activities of multiple robots. In the CAMPOUT, multiple-agent activities and sensor-based controls are derived as group compositions and involve coordination of more basic controllers denoted, for present purposes, as behaviors. The CAMPOUT provides basic mechanistic concepts for representation and execution of distributed group activities. One considers a network of nodes that comprise behaviors (self-contained controllers) augmented with hyper-links, which are used to exchange information between the nodes to achieve coordinated activities. Group behavior is guided by a scripted plan, which encodes a conditional sequence of single-agent activities. Thus, higher-level functionality is composed by coordination of more basic behaviors under the downward task decomposition of a multi-agent planner

Regulation of GluR2 promoter activity by neurotrophic factors via a neuron-restrictive silencer element.

PubMed

Brené, S; Messer, C; Okado, H; Hartley, M; Heinemann, S F; Nestler, E J

2000-05-01

The AMPA glutamate receptor subunit GluR2, which plays a critical role in regulation of AMPA channel function, shows altered levels of expression in vivo after several chronic perturbations. To evaluate the possibility that transcriptional mechanisms are involved, we studied a 1254-nucleotide fragment of the 5'-promoter region of the mouse GluR2 gene in neural-derived cell lines. We focused on regulation of GluR2 promoter activity by two neurotrophic factors, which are known to be altered in vivo in some of the same systems that show GluR2 regulation. Glial-cell line derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) both induced GluR2 promoter activity. This was associated with increased expression of endogenous GluR2 immunoreactivity in the cells as measured by Western blotting. The effect of GDNF and BDNF appeared to be mediated via a NRSE (neuron-restrictive silencer element) present within the GluR2 promoter. The response to these neurotrophic factors was lost upon mutating or deleting this site, but not several other putative response elements present within the promoter. Moreover, overexpression of REST (restrictive element silencer transcription factor; also referred to as NRSF or neuron restrictive silencer factor), which is known to act on NRSEs in other genes to repress gene expression, blocked the ability of GDNF to induce GluR2 promoter activity. However, GDNF did not alter endogenous levels of REST in the cells. Together, these findings suggest that GluR2 expression can be regulated by neurotrophic factors via an apparently novel mechanism involving the NRSE present within the GluR2 gene promoter.

The effects of adolescent methylphenidate exposure on the behavioral and brain-derived neurotrophic factor response to nicotine.

PubMed

Cummins, Elizabeth D; Leedy, Kristen K; Dose, John M; Peterson, Daniel J; Kirby, Seth L; Hernandez, Liza J; Brown, Russell W

2017-01-01

This study analyzed the interaction of adolescent methylphenidate on the behavioral response to nicotine and the effects of these drug treatments on brain-derived neurotrophic factor in the nucleus accumbens and hippocampus in male and female Sprague-Dawley rats. Animals were intraperitoneal administered 1 mg/kg methylphenidate or saline using a "school day" regimen (five days on, two days off) beginning on postnatal day (P)28 and throughout behavioral testing. In Experiment 1, animals were intraperitoneal administered 0.5 mg/kg (free base) nicotine or saline every second day for 10 days from P45-P63 and tested after a three-day drug washout on the forced swim stress task on P67-P68. Results revealed that adolescent methylphenidate blunted nicotine behavioral sensitization. However, methylphenidate-treated rats given saline during sensitization demonstrated decreased latency to immobility and increased immobility time on the forced swim stress task in males that was reduced by nicotine. In Experiment 2, a different set of animals were conditioned to nicotine (0.6 mg/kg free base) or saline using the conditioned place preference behavioral paradigm from P44-P51, and given a preference test on P52. On P53, the nucleus accumbens and hippocampus were analyzed for brain-derived neurotrophic factor. Methylphenidate enhanced nicotine-conditioned place preference in females and nicotine produced conditioned place preference in males and females pre-exposed to saline in adolescence. In addition, methylphenidate and nicotine increased nucleus accumbens brain-derived neurotrophic factor in females and methylphenidate enhanced hippocampus brain-derived neurotrophic factor in males and females. Methylphenidate adolescent exposure using a clinically relevant dose and regimen results in changes in the behavioral and brain-derived neurotrophic factor responses to nicotine in adolescence that are sex-dependent.

Thyroxin treatment protects against white matter injury in the immature brain via brain-derived neurotrophic factor.

PubMed

Hung, Pi-Lien; Huang, Chao-Ching; Huang, Hsiu-Mei; Tu, Dom-Gene; Chang, Ying-Chao

2013-08-01

Low level of thyroid hormone is a strong independent risk factor for white matter (WM) injury, a major cause of cerebral palsy, in preterm infants. Thyroxin upregulates brain-derived neurotrophic factor during development. We hypothesized that thyroxin protected against preoligodendrocyte apoptosis and WM injury in the immature brain via upregulation of brain-derived neurotrophic factor. Postpartum (P) day-7 male rat pups were exposed to hypoxic ischemia (HI) and intraperitoneally injected with thyroxin (T4; 0.2 mg/kg or 1 mg/kg) or normal saline immediately after HI at P9 and P11. WM damage was analyzed for myelin formation, axonal injury, astrogliosis, and preoligodendrocyte apoptosis. Neurotrophic factor expression was assessed by real-time polymerase chain reaction and immunohistochemistry. Neuromotor functions were measured using open-field locomotion (P11 and P21), inclined plane climbing (P11), and beam walking (P21). Intracerebroventricular injection of TrkB-Fc or systemic administration of 7,8-dihydroxyflavone was performed. On P11, the HI group had significantly lower blood T4 levels than the controls. The HI group showed ventriculomegaly and marked reduction of myelin basic protein immunoreactivities in the WM. T4 (1 mg/kg) treatment after HI markedly attenuated axonal injury, astrocytosis, and microgliosis, and increased preoligodendrocyte survival. In addition, T4 treatment significantly increased myelination and selectively upregulated brain-derived neurotrophic factor expression in the WM, and improved neuromotor deficits after HI. The protective effect of T4 on WM myelination and neuromotor performance after HI was significantly attenuated by TrkB-Fc. Systemic 7,8-dihydroxyflavone treatment ameliorated hypomyelination after HI injury. T4 protects against WM injury at both pathological and functional levels via upregulation of brain-derived neurotrophic factor-TrkB signaling in the immature brain.

Neurotrophically Induced Mesenchymal Progenitor Cells Derived from Induced Pluripotent Stem Cells Enhance Neuritogenesis via Neurotrophin and Cytokine Production

PubMed Central

Brick, Rachel M.; Sun, Aaron X.

2017-01-01

Abstract Adult tissue‐derived mesenchymal stem cells (MSCs) are known to produce a number of bioactive factors, including neurotrophic growth factors, capable of supporting and improving nerve regeneration. However, with a finite culture expansion capacity, MSCs are inherently limited in their lifespan and use. We examined here the potential utility of an alternative, mesenchymal‐like cell source, derived from induced pluripotent stem cells, termed induced mesenchymal progenitor cells (MiMPCs). We found that several genes were upregulated and proteins were produced in MiMPCs that matched those previously reported for MSCs. Like MSCs, the MiMPCs secreted various neurotrophic and neuroprotective factors, including brain‐derived neurotrophic factor (BDNF), interleukin‐6 (IL‐6), leukemia inhibitory factor (LIF), osteopontin, and osteonectin, and promoted neurite outgrowth in chick embryonic dorsal root ganglia (DRG) cultures compared with control cultures. Cotreatment with a pharmacological Trk‐receptor inhibitor did not result in significant decrease in MiMPC‐induced neurite outgrowth, which was however inhibited upon Jak/STAT3 blockade. These findings suggest that the MiMPC induction of DRG neurite outgrowth is unlikely to be solely dependent on BDNF, but instead Jak/STAT3 activation by IL‐6 and/or LIF is likely to be critical neurotrophic signaling pathways of the MiMPC secretome. Taken together, these findings suggest MiMPCs as a renewable, candidate source of therapeutic cells and a potential alternative to MSCs for peripheral nerve repair, in view of their ability to promote nerve growth by producing many of the same growth factors and cytokines as Schwann cells and signaling through critical neurotrophic pathways. stem cells translational Medicine 2018;7:45–58 PMID:29215199

Translating neurotrophic and cellular plasticity: from pathophysiology to improved therapeutics for bipolar disorder

PubMed Central

Soeiro-de-Souza, M. G.; Dias, V. V.; Figueira, M. L.; Forlenza, O. V.; Gattaz, W. F.; Zarate, C. A.; Machado-Vieira, R.

2014-01-01

Objective Bipolar disorder (BD) likely involves, at a molecular and cellular level, dysfunctions of critical neurotrophic, cellular plasticity and resilience pathways and neuroprotective processes. Therapeutic properties of mood stabilizers are presumed to result from a restoration of the function of these altered pathways and processes through a wide range of biochemical and molecular effects. We aimed to review the altered pathways and processes implicated in BD, such as neurotrophic factors, mitogen-activated protein kinases, Bcl-2, phosphoinositol signaling, intracellular calcium and glycogen synthase kinase-3. Methods We undertook a literature search of recent relevant journal articles, book chapter and reviews on neurodegeneration and neuroprotection in BD. Search words entered were ‘brain-derived neurotrophic factor,’ ‘Bcl-2,’ ‘mitogen-activated protein kinases,’ ‘neuroprotection,’ ‘calcium,’ ‘bipolar disorder,’ ‘mania,’ and ‘depression.’ Results The most consistent and replicated findings in the pathophysiology of BD may be classified as follows: i) calcium dysregulation, ii) mitochondrial/endoplasmic reticulum dysfunction, iii) glial and neuronal death/atrophy and iv) loss of neurotrophic/plasticity effects in brain areas critically involved in mood regulation. In addition, the evidence supports that treatment with mood stabilizers; in particular, lithium restores these pathophysiological changes. Conclusion Bipolar disorder is associated with impairments in neurotrophic, cellular plasticity and resilience pathways as well as in neuroprotective processes. The evidence supports that treatment with mood stabilizers, in particular lithium, restores these pathophysiological changes. Studies that attempt to prevent (intervene before the onset of the molecular and cellular changes), treat (minimize severity of these deficits over time), and rectify (reverse molecular and cellular deficits) are promising therapeutic strategies for developing improved treatments for bipolar disorder. PMID:22676371

Translating neurotrophic and cellular plasticity: from pathophysiology to improved therapeutics for bipolar disorder.

PubMed

Soeiro-de-Souza, M G; Dias, V V; Figueira, M L; Forlenza, O V; Gattaz, W F; Zarate, C A; Machado-Vieira, R

2012-11-01

Bipolar disorder (BD) likely involves, at a molecular and cellular level, dysfunctions of critical neurotrophic, cellular plasticity and resilience pathways and neuroprotective processes. Therapeutic properties of mood stabilizers are presumed to result from a restoration of the function of these altered pathways and processes through a wide range of biochemical and molecular effects. We aimed to review the altered pathways and processes implicated in BD, such as neurotrophic factors, mitogen-activated protein kinases, Bcl-2, phosphoinositol signaling, intracellular calcium and glycogen synthase kinase-3. We undertook a literature search of recent relevant journal articles, book chapter and reviews on neurodegeneration and neuroprotection in BD. Search words entered were 'brain-derived neurotrophic factor,''Bcl-2,''mitogen-activated protein kinases,''neuroprotection,''calcium,''bipolar disorder,''mania,' and 'depression.' The most consistent and replicated findings in the pathophysiology of BD may be classified as follows: i) calcium dysregulation, ii) mitochondrial/endoplasmic reticulum dysfunction, iii) glial and neuronal death/atrophy and iv) loss of neurotrophic/plasticity effects in brain areas critically involved in mood regulation. In addition, the evidence supports that treatment with mood stabilizers; in particular, lithium restores these pathophysiological changes. Bipolar disorder is associated with impairments in neurotrophic, cellular plasticity and resilience pathways as well as in neuroprotective processes. The evidence supports that treatment with mood stabilizers, in particular lithium, restores these pathophysiological changes. Studies that attempt to prevent (intervene before the onset of the molecular and cellular changes), treat (minimize severity of these deficits over time), and rectify (reverse molecular and cellular deficits) are promising therapeutic strategies for developing improved treatments for bipolar disorder. © 2012 John Wiley & Sons A/S.

Inhibitory Effect of Memantine on Streptozotocin-Induced Insulin Receptor Dysfunction, Neuroinflammation, Amyloidogenesis, and Neurotrophic Factor Decline in Astrocytes.

PubMed

Rajasekar, N; Nath, Chandishwar; Hanif, Kashif; Shukla, Rakesh

2016-12-01

Our earlier studies showed that insulin receptor (IR) dysfunction along with neuroinflammation and amyloidogenesis played a major role in streptozotocin (STZ)-induced toxicity in astrocytes. N-methyl-D-aspartate (NMDA) receptor antagonist-memantine shows beneficial effects in Alzheimer's disease (AD) pathology. However, the protective molecular and cellular mechanism of memantine in astrocytes is not properly understood. Therefore, the present study was undertaken to investigate the effect of memantine on insulin receptors, neurotrophic factors, neuroinflammation, and amyloidogenesis in STZ-treated astrocytes. STZ (100 μM) treatment for 24 h in astrocytes resulted significant decrease in brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and insulin-degrading enzyme (IDE) expression in astrocytes. Treatment with memantine (1-10 μM) improved STZ-induced neurotrophic factor decline (BDNF, GDNF) along with IR dysfunction as evidenced by a significant increase in IR protein expression, phosphorylation of IRS-1, Akt, and GSK-3 α/β in astrocytes. Further, memantine attenuated STZ-induced amyloid precursor protein (APP), β-site APP-cleaving enzyme-1 and amyloid-β 1-42 expression and restored IDE expression in astrocytes. In addition, memantine also displays protective effects against STZ-induced astrocyte activation showed by reduction of inflammatory markers, nuclear factor kappa-B translocation, glial fibrillary acidic protein, cyclooxygenase-2, tumor necrosis factor-α level, and oxidative-nitrostative stress. The results suggest that besides the NMDA receptor antagonisic activity, effect on astroglial IR and neurotrophic factor may also be an important factor in the beneficial effect of memantine in AD pathology. Graphical Abstract Novel neuroprotective mechanisms of memenatine in streptozotocin-induced toxicity in astrocytes.

Intelligent multiagent coordination based on reinforcement hierarchical neuro-fuzzy models.

PubMed

Mendoza, Leonardo Forero; Vellasco, Marley; Figueiredo, Karla

2014-12-01

This paper presents the research and development of two hybrid neuro-fuzzy models for the hierarchical coordination of multiple intelligent agents. The main objective of the models is to have multiple agents interact intelligently with each other in complex systems. We developed two new models of coordination for intelligent multiagent systems, which integrates the Reinforcement Learning Hierarchical Neuro-Fuzzy model with two proposed coordination mechanisms: the MultiAgent Reinforcement Learning Hierarchical Neuro-Fuzzy with a market-driven coordination mechanism (MA-RL-HNFP-MD) and the MultiAgent Reinforcement Learning Hierarchical Neuro-Fuzzy with graph coordination (MA-RL-HNFP-CG). In order to evaluate the proposed models and verify the contribution of the proposed coordination mechanisms, two multiagent benchmark applications were developed: the pursuit game and the robot soccer simulation. The results obtained demonstrated that the proposed coordination mechanisms greatly improve the performance of the multiagent system when compared with other strategies.

NEUROTROPHIC FACTORS IN COMBINATORIAL APPROACHES FOR SPINAL CORD REGENERATION

PubMed Central

McCall, Julianne; Weidner, Norbert; Blesch, Armin

2012-01-01

Axonal regeneration is inhibited by a plethora of different mechanisms in the adult central nervous system (CNS). While neurotrophic factors have been shown to stimulate axonal growth in numerous animal models of nervous system injury, a lack of suitable growth substrates, an insufficient activation of neuron-intrinsic regenerative programs and extracellular inhibitors of regeneration limit the efficacy of neurotrophic factor delivery for anatomical and functional recovery after spinal cord injury. Thus, growth-stimulating factors will likely have to be combined with other treatment approaches to tap into the full potential of growth factor therapy for axonal regeneration. In addition, the temporal and spatial distribution of growth factors have to be tightly controlled to achieve biologically active concentrations, to allow for the chemotropic guidance of axons and to prevent adverse effects related to the widespread distribution of neurotrophic factors. Here, we will review the rationale for combinatorial treatments in axonal regeneration and summarize some recent progress in promoting axonal regeneration in the injured CNS using such approaches. PMID:22526621

Retinal pigment epithelium, age-related macular degeneration and neurotrophic keratouveitis.

PubMed

Bianchi, Enrica; Scarinci, Fabio; Ripandelli, Guido; Feher, Janos; Pacella, Elena; Magliulo, Giuseppe; Gabrieli, Corrado Balacco; Plateroti, Rocco; Plateroti, Pasquale; Mignini, Fiorenzo; Artico, Marco

2013-01-01

Age-related macular degeneration (AMD) is the leading cause of impaired vision and blindness in the aging population. The aims of our studies were to identify qualitative and quantitative alterations in mitochondria in human retinal pigment epithelium (RPE) from AMD patients and controls and to test the protective effects of pigment epithelium-derived factor (PEDF), a known neurotrophic and antiangiogenic substance, against neurotrophic keratouveitis. Histopathological alterations were studied by means of morphometry, light and electron microscopy. Unexpectedly, morphometric data showed that the RPE alterations noted in AMD may also develop in normal aging, 10-15 years later than appearing in AMD patients. Reduced tear secretion, corneal ulceration and leukocytic infiltration were found in capsaicin (CAP)-treated rats, but this effect was significantly attenuated by PEDF. These findings suggest that PEDF accelerated the recovery of tear secretion and also prevented neurotrophic keratouveitis and vitreoretinal inflammation. PEDF may have a clinical application in inflammatory and neovascular diseases of the eye.

Upregulation of Neurotrophic Factors Selectively in Frontal Cortex in Response to Olfactory Discrimination Learning

PubMed Central

Naimark, Ari; Barkai, Edi; Matar, Michael A.; Kaplan, Zeev; Kozlovsky, Nitzan; Cohen, Hagit

2007-01-01

We have previously shown that olfactory discrimination learning is accompanied by several forms of long-term enhancement in synaptic connections between layer II pyramidal neurons selectively in the piriform cortex. This study sought to examine whether the previously demonstrated olfactory-learning-task-induced modifications are preceded by suitable changes in the expression of mRNA for neurotrophic factors and in which brain areas this occurs. Rats were trained to discriminate positive cues in pair of odors for a water reward. The relationship between the learning task and local levels of mRNA for brain-derived neurotrophic factor, tyrosine kinase B, nerve growth factor, and neurotrophin-3 in the frontal cortex, hippocampal subregions, and other regions were assessed 24 hours post olfactory learning. The olfactory discrimination learning activated production of endogenous neurotrophic factors and induced their signal transduction in the frontal cortex, but not in other brain areas. These findings suggest that different brain areas may be preferentially involved in different learning/memory tasks. PMID:17710248

Neurotrophic Natural Products: Chemistry and Biology

PubMed Central

Xu, Jing; Lacoske, Michelle H.

2014-01-01

Neurodegenerative diseases and spinal cord injury affect approximately 50 million people worldwide, bringing the total healthcare cost to over 600 billion dollars per year. Nervous system growth factors, that is, neurotrophins, are a potential solution to these disorders, since they could promote nerve regeneration. An average of 500 publications per year attests to the significance of neurotrophins in biomedical sciences and underlines their potential for therapeutic applications. Nonetheless, the poor pharmacokinetic profile of neurotrophins severely restricts their clinical use. On the other hand, small molecules that modulate neurotrophic activity offer a promising therapeutic approach against neurological disorders. Nature has provided an impressive array of natural products that have potent neurotrophic activities. This Review highlights the current synthetic strategies toward these compounds and summarizes their ability to induce neuronal growth and rehabilitation. It is anticipated that neurotrophic natural products could be used not only as starting points in drug design but also as tools to study the next frontier in biomedical sciences: the brain activity map project. PMID:24353244

Update of Neurotrophic Factors in Neurobiology of Addiction and Future Directions

PubMed Central

Koskela, Maryna; Bäck, Susanne; Võikar, Vootele; Richie, Christopher T.; Domanskyi, Andrii; Harvey, Brandon K.; Airavaara, Mikko

2016-01-01

Drug addiction is a chronic brain disease and drugs of abuse cause long lasting neuroadaptations. Addiction is characterized by the loss of control over drug use despite harmful consequences, and high rates of relapse even after long periods of abstinence. Neurotrophic factors (NTFs) are well known for their actions on neuronal survival in the peripheral nervous system. Moreover, NTFs have been shown to be involved in synaptic plasticity in the brain. Brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) are two of the most studied NTFs and both of them have been reported to increase craving when administered into the mesocorticolimbic dopaminergic system after drug self-administration. Here we review recent data on BDNF and GDNF functions in addiction-related behavior and discuss them in relation to previous findings. Finally, we give an insight into how new technologies could aid in further elucidating the role of these factors in drug addiction. PMID:27189755

The cyclin-dependent kinase inhibitor p57Kip2 regulates cell cycle exit, differentiation, and migration of embryonic cerebral cortical precursors.

PubMed

Tury, Anna; Mairet-Coello, Georges; DiCicco-Bloom, Emanuel

2011-08-01

Mounting evidence indicates cyclin-dependent kinase (CDK) inhibitors (CKIs) of the Cip/Kip family, including p57(Kip2) and p27(Kip1), control not only cell cycle exit but also corticogenesis. Nevertheless, distinct activities of p57(Kip2) remain poorly defined. Using in vivo and culture approaches, we show p57(Kip2) overexpression at E14.5-15.5 elicits precursor cell cycle exit, promotes transition from proliferation to neuronal differentiation, and enhances process outgrowth, while opposite effects occur in p57(Kip2)-deficient precursors. Studies at later ages indicate p57(Kip2) overexpression also induces precocious glial differentiation, suggesting stage-dependent effects. In embryonic cortex, p57(Kip2) overexpression advances cell radial migration and alters postnatal laminar positioning. While both CKIs induce differentiation, p57(Kip2) was twice as effective as p27(Kip1) in inducing neuronal differentiation and was not permissive to astrogliogenic effects of ciliary neurotrophic factor, suggesting that the CKIs differentially modulate cell fate decisions. At molecular levels, although highly conserved N-terminal regions of both CKIs elicit cycle withdrawal and differentiation, the C-terminal region of p57(Kip2) alone inhibits in vivo migration. Furthermore, p57(Kip2) effects on neurogenesis and gliogenesis require the N-terminal cyclin/CDK binding/inhibitory domains, while previous p27(Kip1) studies report cell cycle-independent functions. These observations suggest p57(Kip2) coordinates multiple stages of corticogenesis and exhibits distinct and common activities compared with related family member p27(Kip1).

Transsynaptic trophic effects of steroid hormones in an avian model of adult brain plasticity

PubMed Central

Brenowitz, Eliot A.

2014-01-01

The avian song control system provides an excellent model for studying transsynaptic trophic effects of steroid sex hormones. Seasonal changes in systemic testosterone (T) and its metabolites regulate plasticity of this system. Steroids interact with the neurotrophin brain-derived neurotrophic factor (BDNF) to influence cellular processes of plasticity in nucleus HVC of adult birds, including the addition of newborn neurons. This interaction may also occur transsynpatically; T increases the synthesis of BDNF in HVC, and BDNF protein is then released by HVC neurons on to postsynaptic cells in nucleus RA where it has trophic effects on activity and morphology. Androgen action on RA neurons increases their activity and this has a retrograde trophic effect on the addition of new neurons to HVC. The functional linkage of sex steroids to BDNF may be of adaptive value in regulating the trophic effects of the neurotrophin and coordinating circuit function in reproductively relevant contexts. PMID:25285401

The multiple life of nerve growth factor: tribute to rita levi-montalcini (1909-2012).

PubMed

Aloe, Luigi; Chaldakov, George N

2013-03-01

At the end of the 19(th) century, it was envisaged by Santiago Ramon y Cajal, but not, proven, that life at the neuronal level requires trophic support. The proof was obtained in the early 1950's by work initiated by Rita Levi-Montalcini (RLM) discovering the nerve growth factor (NGF). Today, NGF and its relatives, collectively designated neurotrophins, are well recognized as mediators of multiple biological phenomena in health and disease, ranging from the neurotrophic through immunotrophic and epitheliotrophic to metabotrophic effects. Consequently, NGF and other neurotrophins are implicated in the pathogenesis of a large spectrum of neuronal and non-neuronal diseases, from Alzheimer's and other neurodegenerative diseases to atherosclerosis and other cardiometabolic diseases. Recent studies demonstrated the therapeutic potentials of NGF in these diseases, including ocular and cutaneous diseases. Furthermore, NGF TrkA receptor antagonists emerged as novel drugs for pain, prostate and breast cancer, melanoma, and urinary bladder syndromes. Altogether, NGF's multiple potential in health and disease is briefly described here.

Sera from Children with Autism Induce Autistic Features Which Can Be Rescued with a CNTF Small Peptide Mimetic in Rats

PubMed Central

Kazim, Syed Faraz; Cardenas-Aguayo, Maria del Carmen; Arif, Mohammad; Blanchard, Julie; Fayyaz, Fatima; Grundke-Iqbal, Inge; Iqbal, Khalid

2015-01-01

Autism is a neurodevelopmental disorder characterized clinically by impairments in social interaction and verbal and non-verbal communication skills as well as restricted interests and repetitive behavior. It has been hypothesized that altered brain environment including an imbalance in neurotrophic support during early development contributes to the pathophysiology of autism. Here we report that sera from children with autism which exhibited abnormal levels of various neurotrophic factors induced cell death and oxidative stress in mouse primary cultured cortical neurons. The effects of sera from autistic children were rescued by pre-treatment with a ciliary neurotrophic factor (CNTF) small peptide mimetic, Peptide 6 (P6), which was previously shown to exert its neuroprotective effect by modulating CNTF/JAK/STAT pathway and LIF signaling and by enhancing brain derived neurotrophic factor (BDNF) expression. Similar neurotoxic effects and neuroinflammation were observed in young Wistar rats injected intracerebroventricularly with autism sera within hours after birth. The autism sera injected rats demonstrated developmental delay and deficits in social communication, interaction, and novelty. Both the neurobiological changes and the behavioral autistic phenotype were ameliorated by P6 treatment. These findings implicate the involvement of neurotrophic imbalance during early brain development in the pathophysiology of autism and a proof of principle of P6 as a potential therapeutic strategy for autism. PMID:25769033

Sera from children with autism induce autistic features which can be rescued with a CNTF small peptide mimetic in rats.

PubMed

Kazim, Syed Faraz; Cardenas-Aguayo, Maria Del Carmen; Arif, Mohammad; Blanchard, Julie; Fayyaz, Fatima; Grundke-Iqbal, Inge; Iqbal, Khalid

2015-01-01

Autism is a neurodevelopmental disorder characterized clinically by impairments in social interaction and verbal and non-verbal communication skills as well as restricted interests and repetitive behavior. It has been hypothesized that altered brain environment including an imbalance in neurotrophic support during early development contributes to the pathophysiology of autism. Here we report that sera from children with autism which exhibited abnormal levels of various neurotrophic factors induced cell death and oxidative stress in mouse primary cultured cortical neurons. The effects of sera from autistic children were rescued by pre-treatment with a ciliary neurotrophic factor (CNTF) small peptide mimetic, Peptide 6 (P6), which was previously shown to exert its neuroprotective effect by modulating CNTF/JAK/STAT pathway and LIF signaling and by enhancing brain derived neurotrophic factor (BDNF) expression. Similar neurotoxic effects and neuroinflammation were observed in young Wistar rats injected intracerebroventricularly with autism sera within hours after birth. The autism sera injected rats demonstrated developmental delay and deficits in social communication, interaction, and novelty. Both the neurobiological changes and the behavioral autistic phenotype were ameliorated by P6 treatment. These findings implicate the involvement of neurotrophic imbalance during early brain development in the pathophysiology of autism and a proof of principle of P6 as a potential therapeutic strategy for autism.

Cognitive and hippocampus biochemical changes following sleep deprivation in the adult male rat.

PubMed

Nabaee, Ebrahim; Kesmati, Mahnaz; Shahriari, Ali; Khajehpour, Lotfollah; Torabi, Mozhgan

2018-05-14

Sleep deprivation (SD) influences physiological processes such as cognitive function. The balance of oxidant and antioxidant markers, neurotrophic factors and magnesium are affected by sleep deprivation but there is no difference between pre and post training sleep deprivation. This study was designed to investigate memory retrieval and biochemical factors such as oxidant and antioxidant enzyme, brain-derived neurotrophic factor (BDNF) and magnesium levels in the hippocampus following pre and post-training sleep deprivation. Male Wistar rats (weighing 200 ± 20 g) in below groups were used: control 1, 24, 48 and 72 h SD before training groups, control2, 24 h SD1 after training (being evaluated 24 h after training) and SD2 24 after training (being evaluated 48 h after training). Memory was evaluated 90 min, 24 h or 48 h after training by step-through passive avoidance apparatus. Multiple platforms method was used to induce SD. Oxidant and antioxidant markers including glutathione (GSH), glutathione reductase (GPx), malonedialdehyde (MDA), Total antioxidant concentration, catalase, superoxide dismutase (SOD), magnesium and BDNF were assessed in the hippocampus or/and brain. 72 h pre-training SD impaired short and long-term memory significantly. There was no significant difference in hippocampus oxidant and antioxidant markers compared to control. Hippocampal BDNF and magnesium did not show any changes in all SD groups. Lack of correlation between memory impairment and levels of BDNF, magnesium and/or oxidant and antioxidant balance in the hippocampus is likely to be related to animal locomotor activity in the multiple platforms method. More research is needed to clarify the role of neurochemical systems. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Pharmacokinetics and pharmacodynamics of multiple doses of BG00010, a neurotrophic factor with anti-hyperalgesic effects, in patients with sciatica.

PubMed

Okkerse, Pieter; Hay, Justin L; Versage, Eve; Tang, Yongqiang; Galluppi, Gerald; Ravina, Bernard; Verma, Ajay; Williams, Leslie; Aycardi, Ernesto; Groeneveld, Geert Jan

2016-07-01

BG00010 is a protein in the glial cell line-derived neurotrophic factor (GDNF) family. It is a selective ligand for the GDNF family receptor alpha-3 (GFRα3) co-receptor that normalizes cellular changes resulting from damage or disease, and potentially alleviates neuropathic pain. The main objectives of this study were to evaluate the pharmacokinetic and safety profiles and to determine the effects on pain of ascending doses of intravenous injections of BG00010 in patients with sciatica. This was a randomized, blinded, placebo-controlled multiple-dose study in subjects with sciatica. In Part I (16 patients), four IV dose levels were examined (50, 150, 400, 800 μg kg(-1) ) and in Part II (12 patients), three dose levels were examined (400, 600 and 1200 μg kg(-1) ). Safety and efficacy assessments were used as endpoints. The BG00010 concentration-time data indicated relatively low inter-patient variability and there was a dose-dependent (not dose-proportional) increase in serum exposure from 150 to 1200 μg kg(-1) . The effective half-life was between 40 and 60 h. The most frequently occurring adverse events (AEs) reported by patients receiving BG00010 were headache (67-83%), feeling hot (50-100%), and pruritus (42-67%). Most AEs were mild; no serious AEs or AEs leading to discontinuation occurred. Higher dose regimens of BG00010 resulted in greater pain reduction than placebo or lower dose regimens, although a clear dose-response relationship was not seen. The pharmacokinetic profile of BG00010 was characterized by low intra-patient variability. These data from a small sample suggest that BG00010 may have a benefit for patients with sciatica. © 2016 The British Pharmacological Society.

Transcriptional Regulation of Brain-Derived Neurotrophic Factor (BDNF) by Methyl CpG Binding Protein 2 (MeCP2): a Novel Mechanism for Re-Myelination and/or Myelin Repair Involved in the Treatment of Multiple Sclerosis (MS).

PubMed

KhorshidAhmad, Tina; Acosta, Crystal; Cortes, Claudia; Lakowski, Ted M; Gangadaran, Surendiran; Namaka, Michael

2016-03-01

Multiple sclerosis (MS) is a chronic progressive, neurological disease characterized by the targeted immune system-mediated destruction of central nervous system (CNS) myelin. Autoreactive CD4+ T helper cells have a key role in orchestrating MS-induced myelin damage. Once activated, circulating Th1-cells secrete a variety of inflammatory cytokines that foster the breakdown of blood-brain barrier (BBB) eventually infiltrating into the CNS. Inside the CNS, they become reactivated upon exposure to the myelin structural proteins and continue to produce inflammatory cytokines such as tumor necrosis factor α (TNFα) that leads to direct activation of antibodies and macrophages that are involved in the phagocytosis of myelin. Proliferating oligodendrocyte precursors (OPs) migrating to the lesion sites are capable of acute remyelination but unable to completely repair or restore the immune system-mediated myelin damage. This results in various permanent clinical neurological disabilities such as cognitive dysfunction, fatigue, bowel/bladder abnormalities, and neuropathic pain. At present, there is no cure for MS. Recent remyelination and/or myelin repair strategies have focused on the role of the neurotrophin brain-derived neurotrophic factor (BDNF) and its upstream transcriptional repressor methyl CpG binding protein (MeCP2). Research in the field of epigenetic therapeutics involving histone deacetylase (HDAC) inhibitors and lysine acetyl transferase (KAT) inhibitors is being explored to repress the detrimental effects of MeCP2. This review will address the role of MeCP2 and BDNF in remyelination and/or myelin repair and the potential of HDAC and KAT inhibitors as novel therapeutic interventions for MS.

Modulatory effects of aromatherapy massage intervention on electroencephalogram, psychological assessments, salivary cortisol and plasma brain-derived neurotrophic factor.

PubMed

Wu, Jin-Ji; Cui, Yanji; Yang, Yoon-Sil; Kang, Moon-Seok; Jung, Sung-Cherl; Park, Hyeung Keun; Yeun, Hye-Young; Jang, Won Jung; Lee, Sunjoo; Kwak, Young Sook; Eun, Su-Yong

2014-06-01

Aromatherapy massage is commonly used for the stress management of healthy individuals, and also has been often employed as a therapeutic use for pain control and alleviating psychological distress, such as anxiety and depression, in oncological palliative care patients. However, the exact biological basis of aromatherapy massage is poorly understood. Therefore, we evaluated here the effects of aromatherapy massage interventions on multiple neurobiological indices such as quantitative psychological assessments, electroencephalogram (EEG) power spectrum pattern, salivary cortisol and plasma brain-derived neurotrophic factor (BDNF) levels. A control group without treatment (n = 12) and aromatherapy massage group (n = 13) were randomly recruited. They were all females whose children were diagnosed as attention deficit hyperactivity disorder and followed up in the Department of Psychiatry, Jeju National University Hospital. Participants were treated with aromatherapy massage for 40 min twice per week for 4 weeks (8 interventions). A 4-week-aromatherapy massage program significantly improved all psychological assessment scores in the Stat-Trait Anxiety Index, Beck Depression Inventory and Short Form of Psychosocial Well-being Index. Interestingly, plasma BDNF levels were significantly increased after a 4 week-aromatherapy massage program. Alpha-brain wave activities were significantly enhanced and delta wave activities were markedly reduced following the one-time aromatherapy massage treatment, as shown in the meditation and neurofeedback training. In addition, salivary cortisol levels were significantly reduced following the one-time aromatherapy massage treatment. These results suggest that aromatherapy massage could exert significant influences on multiple neurobiological indices such as EEG pattern, salivary cortisol and plasma BDNF levels as well as psychological assessments. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Effects of Exercise on Progranulin Levels and Gliosis in Progranulin-Insufficient Mice1,2,3

PubMed Central

Arrant, Andrew E.; Patel, Aashka R.

2015-01-01

Abstract Loss-of-function mutations in progranulin (GRN) are one of the most common genetic causes of frontotemporal dementia (FTD), a progressive, fatal neurodegenerative disorder with no available disease-modifying treatments. Through haploinsufficiency, these mutations reduce levels of progranulin, a protein that has neurotrophic and anti-inflammatory effects. Increasing progranulin expression from the intact allele is therefore a potential approach for treating individuals with GRN mutations. Based on the well-known effects of physical exercise on other neurotrophic factors, we hypothesized that exercise might increase brain progranulin levels. We tested this hypothesis in progranulin heterozygous (Grn+/−) mice, which model progranulin haploinsufficiency. We housed wild-type and progranulin-insufficient mice in standard cages or cages with exercise wheels for 4 or 7.5 weeks, and then measured brain and plasma progranulin levels. Although exercise modestly increased progranulin in very young (2-month-old) wild-type mice, this effect was limited to the hippocampus. Exercise did not increase brain progranulin mRNA or protein in multiple regions, nor did it increase plasma progranulin, in 4- to 8-month-old wild-type or Grn+/− mice, across multiple experiments and under conditions that increased hippocampal BDNF and neurogenesis. Grn−/−mice were included in the study to test for progranulin-independent benefits of exercise on gliosis. Exercise attenuated cortical microgliosis in 8-month-old Grn−/−mice, consistent with a progranulin-independent, anti-inflammatory effect of exercise. These results suggest that exercise may have some modest, nonspecific benefits for FTD patients with progranulin mutations, but do not support exercise as a strategy to raise progranulin levels. PMID:26361634

EEG alpha power as an intermediate measure between brain-derived neurotrophic factor Val66Met and depression severity in patients with major depressive disorder.

PubMed

Zoon, Harriët F A; Veth, C P M; Arns, Martijn; Drinkenburg, W H I M; Talloen, Willem; Peeters, Pieter J; Kenemans, J L

2013-06-01

Major depressive disorder has a large impact on patients and society and is projected to be the second greatest global burden of disease by 2020. The brain-derived neurotrophic factor (BDNF) gene is considered to be one of the important factors in the etiology of major depressive disorder. In a recent study, alpha power was found to mediate between BDNF Met and subclinical depressed mood. The current study looked at a population of patients with major depressive disorder (N = 107) to examine the association between the BDNF Val66Met polymorphism, resting state EEG alpha power, and depression severity. For this purpose, repeated-measures analysis of variance, partial correlation, and multiple linear models were used. Results indicated a negative association between parietal-occipital alpha power in the eyes open resting state and depression severity. In addition, Met/Met patients showed lower global absolute alpha power in the eyes closed condition compared with Val-carriers. These findings are in accordance with the previously uncovered pathway between BDNF Val66Met, resting state EEG alpha power, and depression severity. Additional research is needed for the clarification of this tentative pathway and its implication in personalized treatment of major depressive disorder.

Plasma and serum brain-derived neurotrophic factor (BDNF) levels and their association with neurocognition in at-risk mental state, first episode psychosis and chronic schizophrenia patients.

PubMed

Heitz, Ulrike; Papmeyer, Martina; Studerus, Erich; Egloff, Laura; Ittig, Sarah; Andreou, Christina; Vogel, Tobias; Borgwardt, Stefan; Graf, Marc; Eckert, Anne; Riecher-Rössler, Anita

2018-06-25

Brain-derived neurotrophic factor (BDNF) is involved in numerous cognitive processes. Since cognitive deficits are a core feature of psychotic disorders, the investigation of BDNF levels in psychosis and their correlation with cognition has received increased attention. However, there are no studies investigating BDNF levels in individuals with an at-risk mental state (ARMS) for psychosis. Hence, the aims of the present study were: (1) assessing peripheral BDNF levels across different (potential) stages of psychosis; (2) investigating their association with cognition. Plasma and serum BDNF levels and neuropsychological performance were assessed in 16 ARMS, six first-episode psychosis (FEP), and 11 chronic schizophrenia (CS) patients. Neuropsychological assessment covered intelligence, verbal memory, working memory, attention and executive functioning. Both plasma and serum BDNF levels were highest in CS, intermediate in FEP and lowest in ARMS. Multiple regression analysis revealed a significant positive association of plasma BDNF levels with planning ability across all groups. The lower peripheral BDNF levels in ARMS compared to FEP and CS might point towards an important drop of this neurotrophin prior to the onset of frank psychosis. The associations of peripheral BDNF with planning-abilities match previous findings.

Detoxified extract of Rhus verniciflua stokes inhibits rotenone-induced apoptosis in human dopaminergic cells, SH-SY5Y.

PubMed

Sapkota, Kumar; Kim, Seung; Park, Se-Eun; Kim, Sung-Jun

2011-03-01

Rhus verniciflua Stokes (RVS), traditionally used as a food supplement and in traditional herbal medicine for centuries in Korea, is known to possess various pharmacological properties. Environmental neurotoxins such as rotenone, a specific inhibitor of complex I provide models of Parkinson's disease (PD) both in vivo and in vitro. In this study, we investigated the neuroprotective effect of RVS against rotenone-induced toxicity in human dopaminergic cells, SH-SY5Y. Cells exposed to rotenone for 24 h-induced cellular injury and apoptotic cell death. Pretreatment of cells with RVS provided significant protection to SH-SY5Y cells. Further, RVS offered remarkable protection against rotenone-induced oxidative stress and markedly inhibited mitochondrial membrane potential (MMP) disruption. RVS also attenuated the up-regulation of Bax, Caspase-9 and Caspase-3 and down-regulation of Bcl-2. Moreover, pretreatment with RVS prevented the decrease in tyrosine hydroxylase (TH) levels in SH-SY5Y cells. Interestingly, RVS conferred profound protection to human dopaminergic cells by preventing the downregulation of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF). These results suggest that RVS may protect dopaminergic neurons against rotenone-induced apoptosis by multiple functions and contribute to neuroprotection in neurodegenerative diseases, such as PD.

A data-driven approach for evaluating multi-modal therapy in traumatic brain injury

PubMed Central

Haefeli, Jenny; Ferguson, Adam R.; Bingham, Deborah; Orr, Adrienne; Won, Seok Joon; Lam, Tina I.; Shi, Jian; Hawley, Sarah; Liu, Jialing; Swanson, Raymond A.; Massa, Stephen M.

2017-01-01

Combination therapies targeting multiple recovery mechanisms have the potential for additive or synergistic effects, but experimental design and analyses of multimodal therapeutic trials are challenging. To address this problem, we developed a data-driven approach to integrate and analyze raw source data from separate pre-clinical studies and evaluated interactions between four treatments following traumatic brain injury. Histologic and behavioral outcomes were measured in 202 rats treated with combinations of an anti-inflammatory agent (minocycline), a neurotrophic agent (LM11A-31), and physical therapy consisting of assisted exercise with or without botulinum toxin-induced limb constraint. Data was curated and analyzed in a linked workflow involving non-linear principal component analysis followed by hypothesis testing with a linear mixed model. Results revealed significant benefits of the neurotrophic agent LM11A-31 on learning and memory outcomes after traumatic brain injury. In addition, modulations of LM11A-31 effects by co-administration of minocycline and by the type of physical therapy applied reached statistical significance. These results suggest a combinatorial effect of drug and physical therapy interventions that was not evident by univariate analysis. The study designs and analytic techniques applied here form a structured, unbiased, internally validated workflow that may be applied to other combinatorial studies, both in animals and humans. PMID:28205533

A data-driven approach for evaluating multi-modal therapy in traumatic brain injury.

PubMed

Haefeli, Jenny; Ferguson, Adam R; Bingham, Deborah; Orr, Adrienne; Won, Seok Joon; Lam, Tina I; Shi, Jian; Hawley, Sarah; Liu, Jialing; Swanson, Raymond A; Massa, Stephen M

2017-02-16

Combination therapies targeting multiple recovery mechanisms have the potential for additive or synergistic effects, but experimental design and analyses of multimodal therapeutic trials are challenging. To address this problem, we developed a data-driven approach to integrate and analyze raw source data from separate pre-clinical studies and evaluated interactions between four treatments following traumatic brain injury. Histologic and behavioral outcomes were measured in 202 rats treated with combinations of an anti-inflammatory agent (minocycline), a neurotrophic agent (LM11A-31), and physical therapy consisting of assisted exercise with or without botulinum toxin-induced limb constraint. Data was curated and analyzed in a linked workflow involving non-linear principal component analysis followed by hypothesis testing with a linear mixed model. Results revealed significant benefits of the neurotrophic agent LM11A-31 on learning and memory outcomes after traumatic brain injury. In addition, modulations of LM11A-31 effects by co-administration of minocycline and by the type of physical therapy applied reached statistical significance. These results suggest a combinatorial effect of drug and physical therapy interventions that was not evident by univariate analysis. The study designs and analytic techniques applied here form a structured, unbiased, internally validated workflow that may be applied to other combinatorial studies, both in animals and humans.

Developmental Thyroid Hormone Insufficiency Reduces Expression of Brain-Derived Neurotrophic Factor (BDNF) in Adults But Not in Neonates

EPA Science Inventory

Brain-derived neurotrophic factor (BDNF) is a neurotrophin critical for many developmental and physiological aspects of CNS function. Severe hypothyroidism in the early neonatal period results in developmental and cognitive impairments and reductions in mRNA and protein expressio...

REGULATION OF BRAIN-DERIVED NEUROTROPHIC FACTOR MESSENGER RNA LEVELS IN AVIAN HYPOTHALAMIC SLICE CULTURES. (R825294)

EPA Science Inventory

Mechanisms regulating the expression of brain-derived neurotrophic factor, a member of the neurotrophin family, have been extensively studied in the rat cerebral cortex, hippocampus and cerebellum. In contrast, little is known regarding the regulation of this growth factor in ...

Excessive Astrocyte-Derived Neurotrophin-3 Contributes to the Abnormal Neuronal Dendritic Development in a Mouse Model of Fragile X Syndrome

PubMed Central

Guo, Yan-yan; Liu, Shui-bing; Wu, Yu-mei; Li, Xiao-qiang; Zhao, Ming-gao

2012-01-01

Fragile X syndrome (FXS) is a form of inherited mental retardation in humans that results from expansion of a CGG repeat in the Fmr1 gene. Recent studies suggest a role of astrocytes in neuronal development. However, the mechanisms involved in the regulation process of astrocytes from FXS remain unclear. In this study, we found that astrocytes derived from a Fragile X model, the Fmr1 knockout (KO) mouse which lacks FMRP expression, inhibited the proper elaboration of dendritic processes of neurons in vitro. Furthermore, astrocytic conditioned medium (ACM) from KO astrocytes inhibited proper dendritic growth of both wild-type (WT) and KO neurons. Inducing expression of FMRP by transfection of FMRP vectors in KO astrocytes restored dendritic morphology and levels of synaptic proteins. Further experiments revealed elevated levels of the neurotrophin-3 (NT-3) in KO ACM and the prefrontal cortex of Fmr1 KO mice. However, the levels of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), and ciliary neurotrophic factor (CNTF) were normal. FMRP has multiple RNA–binding motifs and is involved in translational regulation. RNA–binding protein immunoprecipitation (RIP) showed the NT-3 mRNA interacted with FMRP in WT astrocytes. Addition of high concentrations of exogenous NT-3 to culture medium reduced the dendrites of neurons and synaptic protein levels, whereas these measures were ameliorated by neutralizing antibody to NT-3 or knockdown of NT-3 expression in KO astrocytes through short hairpin RNAs (shRNAs). Prefrontal cortex microinjection of WT astrocytes or NT-3 shRNA infected KO astrocytes rescued the deficit of trace fear memory in KO mice, concomitantly decreased the NT-3 levels in the prefrontal cortex. This study indicates that excessive NT-3 from astrocytes contributes to the abnormal neuronal dendritic development and that astrocytes could be a potential therapeutic target for FXS. PMID:23300470

Keep meaning in conversational coordination

PubMed Central

Cuffari, Elena C.

2014-01-01

Coordination is a widely employed term across recent quantitative and qualitative approaches to intersubjectivity, particularly approaches that give embodiment and enaction central explanatory roles. With a focus on linguistic and bodily coordination in conversational contexts, I review the operational meaning of coordination in recent empirical research and related theorizing of embodied intersubjectivity. This discussion articulates what must be involved in treating linguistic meaning as dynamic processes of coordination. The coordination approach presents languaging as a set of dynamic self-organizing processes and actions on multiple timescales and across multiple modalities that come about and work in certain domains (those jointly constructed in social, interactive, high-order sense-making). These processes go beyond meaning at the level that is available to first-person experience. I take one crucial consequence of this to be the ubiquitously moral nature of languaging with others. Languaging coordinates experience, among other levels of behavior and event. Ethical effort is called for by the automatic autonomy-influencing forces of languaging as coordination. PMID:25520693

Human obesity associated with an intronic SNP in the brain-derived neurotrophic factor locus

USDA-ARS?s Scientific Manuscript database

Brain-derived neurotrophic factor (BDNF) plays a key role in energy balance. In population studies, SNPs of the BDNF locus have been linked to obesity, but the mechanism by which these variants cause weight gain is unknown. Here, we examined human hypothalamic BDNF expression in association with 44 ...

Brain-derived neurotrophic factor in human subjects with function-altering melanocortin-4 receptor variants

USDA-ARS?s Scientific Manuscript database

In rodents, hypothalamic brain-derived neurotrophic factor (BDNF) expression appears to be regulated by melanocortin-4 receptor (MC4R) activity. The impact of MC4R genetic variation on circulating BDNF in humans is unknown. The objective of this study is to compare BDNF concentrations of subjects wi...

Brain-Derived Neurotrophic Factor Levels in Autism: A Systematic Review and Meta-Analysis

ERIC Educational Resources Information Center

Saghazadeh, Amene; Rezaei, Nima

2017-01-01

Brain-derived neurotrophic factor (BDNF) plays an important role in activity-dependent synaptic plasticity. Altered blood BDNF levels have been frequently identified in people with autism spectrum disorders (ASD). There are however wide discrepancies in the evidence. Therefore, we performed the present systematic review and meta-analysis aimed at…

Lactoferrin and prematurity: a promising milk protein?

PubMed

Ochoa, Theresa J; Sizonenko, Stéphane V

2017-02-01

Lactoferrin (Lf) is the major whey protein in milk, with multiple beneficial health effects including direct antimicrobial activities, anti-inflammatory effects, and iron homeostasis. Oral Lf supplementation in human preterm infants has been shown to reduce the incidence of sepsis and necrotizing enterocolitis. In preclinical models of antenatal stress and perinatal brain injury, bovine Lf protected the developing brain from neuronal loss, improved connectivity, increased neurotrophic factors, and decreased inflammation. It also supported brain development and cognition. Further, Lf can prevent preterm delivery by reducing proinflammatory factors and inhibiting premature cervix maturation. We review here the latest research on Lf in the field of neonatology.

Protocol for culturing low density pure rat hippocampal neurons supported by mature mixed neuron cultures.

PubMed

Yang, Qian; Ke, Yini; Luo, Jianhong; Tang, Yang

2017-02-01

primary hippocampal neuron cultures allow for subcellular morphological dissection, easy access to drug treatment and electrophysiology analysis of individual neurons, and is therefore an ideal model for the study of neuron physiology. While neuron and glia mixed cultures are relatively easy to prepare, pure neurons are particular hard to culture at low densities which are suitable for morphology studies. This may be due to a lack of neurotrophic factors such as brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT3) and Glial cell line-derived neurotrophic factor (GDNF). In this study we used a two step protocol in which neuron-glia mixed cultures were initially prepared for maturation to support the growth of young neurons plated at very low densities. Our protocol showed that neurotrophic support resulted in physiologically functional hippocampal neurons with larger cell body, increased neurite length and decreased branching and complexity compared to cultures prepared using a conventional method. Our protocol provides a novel way to culture highly uniformed hippocampal neurons for acquiring high quality, neuron based data. Copyright © 2016 Elsevier B.V. All rights reserved.

Alarin-induced antidepressant-like effects and their relationship with hypothalamus-pituitary-adrenal axis activity and brain derived neurotrophic factor levels in mice.

PubMed

Wang, Ming; Chen, Qian; Li, Mei; Zhou, Wei; Ma, Tengfei; Wang, Yun; Gu, Shuling

2014-06-01

Alarin is a newly identified member of the galanin family of peptides. Galanin has been shown to exert regulatory effects on depression. Similar to galanin in distribution, alarin is also expressed in the medial amygdala and hypothalamus, i.e., regions interrelated with depression. However, it remains a puzzle whether alarin is involved in depression. Accordingly, we established the depression-like mouse model using behavioral tests to ascertain the possible involvement of alarin, with fluoxetine as a positive control. With the positive antidepressant-like effects of alarin, we further examined its relationship to HPA axis activity and brain-derived neurotrophic factor (BDNF) levels in different brain areas in a chronic unpredictable mild stress (CUMS) paradigm. In the acute studies, alarin produced a dose-related reduction in the immobility duration in tail suspension test (TST) in mice. In the open-field test, intracerebroventricular (i.c.v.) injection of alarin (1.0 nmol) did not impair locomotion or motor coordination in the treated mice. In the CUMS paradigm, alarin administration (1.0 nmol, i.c.v.) significantly improved murine behaviors (FST and locomotor activity), which was associated with a decrease in corticotropin-releasing hormone (CRH) mRNA levels in the hypothalamus, as well as a decline in serum levels of CRH, adrenocorticotropic hormone (ACTH) and corticosterone (CORT), all of which are key hormones of the HPA axis. Furthermore, alarin upregulated BDNF mRNA levels in the prefrontal cortex and hippocampus. These findings suggest that alarin may potentiate the development of new antidepressants, which would be further secured with the identification of its receptor(s). Copyright © 2014 Elsevier Inc. All rights reserved.

Chronic stress increases pituitary adenylate cyclase-activating peptide (PACAP) and brain-derived neurotrophic factor (BDNF) mRNA expression in the bed nucleus of the stria terminalis (BNST): roles for PACAP in anxiety-like behavior

PubMed Central

Hammack, Sayamwong E.; Cheung, Joseph; Rhodes, Kimberly M.; Schutz, Kristin C.; Falls, William A.; Braas, Karen M.; May, Victor

2009-01-01

Exposure to chronic stress has been argued to produce maladaptive anxiety-like behavioral states, and many of the brain regions associated with stressor responding also mediate anxiety-like behavior. Pituitary adenylate cyclase activating polypeptide (PACAP) and its specific G protein-coupled PAC1 receptor have been associated with many of these stress- and anxiety-associated brain regions, and signaling via this peptidergic system may facilitate the neuroplasticity associated with pathological affective states. Here we investigated whether chronic stress increased transcript expression for PACAP, PAC1 receptor, brain-derived neurotrophic factor (BDNF), and tyrosine receptor kinase B (TrkB) in several nuclei. In rats exposed to a 7 day chronic variate stress paradigm, chronic stress enhanced baseline startle responding induced by handling and exposure to bright lights. Following chronic stress, quantitative transcript assessments of brain regions demonstrated dramatic increases in PACAP and PAC1 receptor, BDNF, and TrkB receptor mRNA expression selectively in the dorsal aspect of the anterolateral bed nucleus of the stria terminalis (dBNST). Related vasoactive intestinal peptide (VIP) and VPAC receptor, and other stress peptide transcript levels were not altered compared to controls. Moreover, acute PACAP38 infusion into the dBNST resulted in a robust dose-dependent anxiogenic response on baseline startle responding that persisted for 7 days. PACAP/PAC1 receptor signaling has established trophic functions and its coordinate effects with chronic stress-induced dBNST BDNF and TrkB transcript expression may underlie the maladaptive BNST remodeling and plasticity associated with anxiety-like behavior. PMID:19181454

The Effect of Repeated Electroacupuncture Analgesia on Neurotrophic and Cytokine Factors in Neuropathic Pain Rats

PubMed Central

Wang, Junying; Duanmu, Chenlin; Feng, Xiumei; Yan, Yaxia

2016-01-01

Chronic pain is a common disability influencing quality of life. Results of previous studies showed that acupuncture has a cumulative analgesic effect, but the relationship with spinal cytokines neurotrophic factors released by astrocytes remains unknown. The present study was designed to observe the effect of electroacupuncture (EA) treatment on spinal cytokines neurotrophic factors in chronic neuropathic pain rats. The chronic neuropathic pain was established by chronic constrictive injury (CCI). EA treatment was applied at Zusanli (ST36) and Yanglingquan (GB34) (both bilateral) once a day, for 30 min. IL-1β mRNA, TNF-α mRNA, and IL-1 mRNA were detected by quantitative real-time PCR, and the proteins of BDNF, NGF, and NT3/4 were detected by Western blot. The expression levels of cytokines such as IL-1β mRNA, TNF-α mRNA, IL-6 mRNA, and neurotrophic factors such as BDNF, NGF, and NT3/4 in the spinal cord were increased significantly after CCI. The astrocytes released more IL-1β and BDNF after CCI. Repeated EA treatment could suppress the elevated expression of IL-1β mRNA, TNFα mRNA, and BDNF, NGF, and NT3/4 but had no effect on IL-6 mRNA. It is suggested that cytokines and neurotrophic factors which may be closely associated with astrocytes participated in the process of EA relieving chronic pain. PMID:27800006

Interleukin-10 Protection against Lipopolysaccharide-Induced Neuro-Inflammation and Neurotoxicity in Ventral Mesencephalic Cultures

PubMed Central

Zhu, Yan; Chen, Xiao; Liu, Zhan; Peng, Yu-Ping; Qiu, Yi-Hua

2015-01-01

Interleukin (IL)-10, an anti-inflammatory cytokine, is expressed in the brain and can inhibit microglial activation. Herein, we utilized lipopolysaccharide (LPS)-induced inflammatory Parkinson’s disease (PD) cell model to determine whether microglia and astrocytes are necessary targets for IL-10 neuroprotection. Primary ventral mesencephalic (VM) cultures with different composition of neurons, microglia and astrocytes were prepared. The cells were exposed to IL-10 (15, 50 or 150 ng/mL) 1 h prior to LPS (50 ng/mL) treatment. LPS induced dopaminergic and non-dopaminergic neuronal loss in VM cultures, VM neuron-enriched cultures, and neuron-microglia co-cultures, but not in neuron-astrocyte co-cultures. IL-10 reduced LPS-induced neuronal loss particularly in single VM neuron cultures. Pro-inflammatory mediators (TNF-α, IL-1β, inducible nitric oxide synthase and cyclooxygenase-2) were upregulated in both neuron-microglia and neuron-astrocyte co-cultures by LPS. In contrast, neurotrophic factors (brain-derived neurotrophic factor, insulin-like growth factor-1 or glial cell-derived neurotrophic factor) were downregulated in neuron-microglia co-cultures, but upregulated in neuron-astrocyte co-cultures by LPS. IL-10 reduced both the increase in production of the pro-inflammatory mediators and the decrease in production of the neurotrophic factors induced by LPS. These results suggest that astrocytes can balance LPS neurotoxicity by releasing more neurotrophic factors and that IL-10 exerts neuroprotective property by an extensive action including direct on neurons and indirect via inhibiting microglial activation. PMID:26729090

Interleukin-10 Protection against Lipopolysaccharide-Induced Neuro-Inflammation and Neurotoxicity in Ventral Mesencephalic Cultures.

PubMed

Zhu, Yan; Chen, Xiao; Liu, Zhan; Peng, Yu-Ping; Qiu, Yi-Hua

2015-12-28

Interleukin (IL)-10, an anti-inflammatory cytokine, is expressed in the brain and can inhibit microglial activation. Herein, we utilized lipopolysaccharide (LPS)-induced inflammatory Parkinson's disease (PD) cell model to determine whether microglia and astrocytes are necessary targets for IL-10 neuroprotection. Primary ventral mesencephalic (VM) cultures with different composition of neurons, microglia and astrocytes were prepared. The cells were exposed to IL-10 (15, 50 or 150 ng/mL) 1 h prior to LPS (50 ng/mL) treatment. LPS induced dopaminergic and non-dopaminergic neuronal loss in VM cultures, VM neuron-enriched cultures, and neuron-microglia co-cultures, but not in neuron-astrocyte co-cultures. IL-10 reduced LPS-induced neuronal loss particularly in single VM neuron cultures. Pro-inflammatory mediators (TNF-α, IL-1β, inducible nitric oxide synthase and cyclooxygenase-2) were upregulated in both neuron-microglia and neuron-astrocyte co-cultures by LPS. In contrast, neurotrophic factors (brain-derived neurotrophic factor, insulin-like growth factor-1 or glial cell-derived neurotrophic factor) were downregulated in neuron-microglia co-cultures, but upregulated in neuron-astrocyte co-cultures by LPS. IL-10 reduced both the increase in production of the pro-inflammatory mediators and the decrease in production of the neurotrophic factors induced by LPS. These results suggest that astrocytes can balance LPS neurotoxicity by releasing more neurotrophic factors and that IL-10 exerts neuroprotective property by an extensive action including direct on neurons and indirect via inhibiting microglial activation.

The positive cognitive impact of aerobic fitness is associated with peripheral inflammatory and brain-derived neurotrophic biomarkers in young adults.

PubMed

Hwang, Jungyun; Castelli, Darla M; Gonzalez-Lima, F

2017-10-01

There is ample evidence for supporting the positive impact of aerobic fitness on cognitive function, but little is known about the physiological mechanisms. The objective of this study was to investigate whether the positive cognitive impact of aerobic fitness is associated with inflammatory and neurotrophic peripheral biomarkers in young adults aged 18 to 29years (n=87). For the objective assessment of aerobic fitness, we measured maximal oxygen uptake (VO 2 max) as a parametric measure of cardiorespiratory capacity. We demonstrated that young adults with the higher levels of VO 2 max performed better on computerized cognitive tasks assessing sustained attention and working memory. This positive VO 2 max-cognitive performance association existed independently of confounders (e.g., years of education, intelligence scores) but was significantly dependent on resting peripheral blood levels of inflammatory (C-reactive protein, CRP) and neurotrophic (brain-derived neurotrophic factor, BDNF) biomarkers. Statistical models showed that CRP was a mediator of the effect of VO 2 max on working memory. Further, BDNF was a moderator of the effect of VO 2 max on working memory. These mediating and moderating effects occurred in individuals with higher levels of aerobic fitness. The results suggest that higher aerobic fitness, as measured by VO 2 max, is associated with enhanced cognitive functioning and favorable resting peripheral levels of inflammatory and brain-derived neurotrophic biomarkers in young adults. Copyright © 2017 Elsevier Inc. All rights reserved.

[6]-shogaol attenuates neuronal apoptosis in hydrogen peroxide-treated astrocytes through the up-regulation of neurotrophic factors.

PubMed

Kim, Sokho; Kwon, Jungkee

2013-12-01

Neuronal apoptosis induced by oxidative stress is a prominent feature of neurodegenerative disorders. [6]-shogaol, a bio-active compound in ginger, possesses potent anti-inflammatory actions and has recently emerged as a potential therapeutic agent for neurodegenerative disorders. However, the effects of [6]-shogaol on astroglial apoptosis following exogenously induced oxidative stress has not yet been investigated. Here, we show that the anti-apoptotic activity of [6]-shogaol in astrocytes following exposure to hydrogen peroxide (H2 O2 ) involves a marked up-regulation of neurotrophic factors such as nerve growth factor, glial cell line-derived neurotrophic factor, and brain-derived neurotrophic factor. Astrocytes co-treated with [6]-shogaol and H2 O2 for 1 h showed decrease in reactive oxygen species production compared with those only treated with H2 O2 . Moreover, [6]-shogaol counteracted the reduced expression of ERK1/2 in H2 O2 -treated astrocytes and protected these cells from oxidative stress and apoptosis by attenuating the impairment of mitochondrial function proteins such as Bcl-2 and Bcl-xL. Additionally, [6]-shogaol inhibits the expression of the apoptotic proteins Bax and caspase-3 in H2 O2 -treated astrocytes. This data suggest that following oxidative stress, [6]-shogaol protects astrocytes from oxidative damage through the up-regulating levels of neurotrophic factors. These findings provide further support for the use of [6]-shogaol as a therapeutic agent in neurodegenerative disorders. Copyright © 2013 John Wiley & Sons, Ltd.

Neural progenitor cell implants modulate vascular endothelial growth factor and brain-derived neurotrophic factor expression in rat axotomized neurons.

PubMed

Talaverón, Rocío; Matarredona, Esperanza R; de la Cruz, Rosa R; Pastor, Angel M

2013-01-01

Axotomy of central neurons leads to functional and structural alterations which largely revert when neural progenitor cells (NPCs) are implanted in the lesion site. The new microenvironment created by NPCs in the host tissue might modulate in the damaged neurons the expression of a high variety of molecules with relevant roles in the repair mechanisms, including neurotrophic factors. In the present work, we aimed to analyze changes in neurotrophic factor expression in axotomized neurons induced by NPC implants. For this purpose, we performed immunofluorescence followed by confocal microscopy analysis for the detection of vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and nerve growth factor (NGF) on brainstem sections from rats with axotomy of abducens internuclear neurons that received NPC implants (implanted group) or vehicle injections (axotomized group) in the lesion site. Control abducens internuclear neurons were strongly immunoreactive to VEGF and BDNF but showed a weak staining for NT-3 and NGF. Comparisons between groups revealed that lesioned neurons from animals that received NPC implants showed a significant increase in VEGF content with respect to animals receiving vehicle injections. However, the immunoreactivity for BDNF, which was increased in the axotomized group as compared to control, was not modified in the implanted group. The modifications induced by NPC implants on VEGF and BDNF content were specific for the population of axotomized abducens internuclear neurons since the neighboring abducens motoneurons were not affected. Similar levels of NT-3 and NGF immunolabeling were obtained in injured neurons from axotomized and implanted animals. Among all the analyzed neurotrophic factors, only VEGF was expressed by the implanted cells in the lesion site. Our results point to a role of NPC implants in the modulation of neurotrophic factor expression by lesioned central neurons, which might contribute to the restorative effects of these implants.

Temporal Coordination and Adaptation to Rate Change in Music Performance

ERIC Educational Resources Information Center

Loehr, Janeen D.; Large, Edward W.; Palmer, Caroline

2011-01-01

People often coordinate their actions with sequences that exhibit temporal variability and unfold at multiple periodicities. We compared oscillator- and timekeeper-based accounts of temporal coordination by examining musicians' coordination of rhythmic musical sequences with a metronome that gradually changed rate at the end of a musical phrase…

Pathophysiology of drug-induce peripheral neuropathy in patients with multiple myeloma.

PubMed

Luczkowska, K; Litwinska, Z; Paczkowska, E; Machalinski, B

2018-04-01

Multiple myeloma (MM) is a disease of unknown, complex etiology that affects primarily older adults. The course of the disease and the patients' survival time are very heterogeneous, but over the last decade, clear progress in the treatment of this incurable disease has been observed. Therapeutics that have proven to be highly effective include the immunomodulatory drug thalidomide and its newer analogs, lenalidomide and pomalidomide, as well as the proteasome inhibitors bortezomib and carfilzomib. However, the administration of some of the treatments, e.g., thalidomide or bortezomib, has also been associated with the occurrence of a serious and common adverse effect, drug-induced peripheral neuropathy. The mechanism of the development of the peripheral neuropathy is poorly understood. Nevertheless, one of its potential causes could be inadequate concentrations of crucial trophic factors, including neurotrophic and/or angiogenic factors, which are responsible for the proliferation, differentiation, survival and death of neuronal and nonneuronal cells.

Differential Regulation of Brain-Derived Neurotrophic Factor Transcripts during the Consolidation of Fear Learning

ERIC Educational Resources Information Center

Ressler, Kerry J.; Rattiner, Lisa M.; Davis, Michael

2004-01-01

Brain-derived neurotrophic factor (BDNF) has been implicated as a molecular mediator of learning and memory. The BDNF gene contains four differentially regulated promoters that generate four distinct mRNA transcripts, each containing a unique noncoding 5[prime]-exon and a common 3[prime]-coding exon. This study describes novel evidence for the…

Gray Matter Volume in Adolescent Anxiety: An Impact of the Brain-Derived Neurotrophic Factor Val[superscript 66]Met Polymorphism?

ERIC Educational Resources Information Center

Mueller, Sven C.; Aouidad, Aveline; Gorodetsky, Elena; Goldman, David; Pine, Daniel S.; Ernst, Monique

2013-01-01

Objective: Minimal research links anxiety disorders in adolescents to regional gray matter volume (GMV) abnormalities and their modulation by genetic factors. Prior research suggests that a brain-derived neurotrophic factor (BNDF) Val[superscript 66]Met polymorphism may modulate such brain morphometry profiles. Method: Using voxel-based…

Assembly and activation of neurotrophic factor receptor complexes.

PubMed

Simi, Anastasia; Ibáñez, Carlos F

2010-04-01

Neurotrophic factors play important roles in the development and function of both neuronal and glial elements of the central and peripheral nervous systems. Their functional diversity is in part based on their ability to interact with alternative complexes of receptor molecules. This review focuses on our current understanding of the mechanisms that govern the assembly and activation of neurotrophic factor receptor complexes. The realization that many, if not the majority, of these complexes exist in a preassembled form at the plasma membrane has forced the revision of classical ligand-mediated oligomerization models, and led to the discovery of novel mechanisms of receptor activation and generation of signaling diversity which are likely to be shared by many different classes of receptors.

Units Coordination and the Construction of Improper Fractions: A Revision of the Splitting Hypothesis

ERIC Educational Resources Information Center

Hackenberg, Amy J.

2007-01-01

This article communicates findings from a year-long constructivist teaching experiment about the relationship between four sixth-grade students' multiplicative structures and their construction of improper fractions. Students' multiplicative structures are the units coordinations that they can take as given prior to activity--i.e., the units…

Quadrupedal gaits in hexapod animals - inter-leg coordination in free-walking adult stick insects.

PubMed

Grabowska, Martyna; Godlewska, Elzbieta; Schmidt, Joachim; Daun-Gruhn, Silvia

2012-12-15

The analysis of inter-leg coordination in insect walking is generally a study of six-legged locomotion. For decades, the stick insect Carausius morosus has been instrumental for unravelling the rules and mechanisms that control leg coordination in hexapeds. We analysed inter-leg coordination in C. morosus that freely walked on straight paths on plane surfaces with different slopes. Consecutive 1.7 s sections were assigned inter-leg coordination patterns (which we call gaits) based on footfall patterns. Regular gaits, i.e. wave, tetrapod or tripod gaits, occurred in different proportions depending on surface slopes. Tetrapod gaits were observed most frequently, wave gaits only occurred on 90 deg inclining slopes and tripod gaits occurred most often on 15 deg declining slopes, i.e. in 40% of the sections. Depending on the slope, 36-66% of the sections were assigned irregular gaits. Irregular gaits were mostly due to multiple stepping by the front legs, which is perhaps probing behaviour, not phase coupled to the middle legs' cycles. In irregular gaits, middle leg and hindleg coordination was regular, related to quadrupedal walk and wave gaits. Apparently, front legs uncouple from and couple to the walking system without compromising middle leg and hindleg coordination. In front leg amputees, the remaining legs were strictly coordinated. In hindleg and middle leg amputees, the front legs continued multiple stepping. The coordination of middle leg amputees was maladapted, with front legs and hindlegs performing multiple steps or ipsilateral legs being in simultaneous swing. Thus, afferent information from middle legs might be necessary for a regular hindleg stepping pattern.

Estimating Accurate Target Coordinates with Magnetic Resonance Images by Using Multiple Phase-Encoding Directions during Acquisition.

PubMed

Kim, Minsoo; Jung, Na Young; Park, Chang Kyu; Chang, Won Seok; Jung, Hyun Ho; Chang, Jin Woo

2018-06-01

Stereotactic procedures are image guided, often using magnetic resonance (MR) images limited by image distortion, which may influence targets for stereotactic procedures. The aim of this work was to assess methods of identifying target coordinates for stereotactic procedures with MR in multiple phase-encoding directions. In 30 patients undergoing deep brain stimulation, we acquired 5 image sets: stereotactic brain computed tomography (CT), T2-weighted images (T2WI), and T1WI in both right-to-left (RL) and anterior-to-posterior (AP) phase-encoding directions. Using CT coordinates as a reference, we analyzed anterior commissure and posterior commissure coordinates to identify any distortion relating to phase-encoding direction. Compared with CT coordinates, RL-directed images had more positive x-axis values (0.51 mm in T1WI, 0.58 mm in T2WI). AP-directed images had more negative y-axis values (0.44 mm in T1WI, 0.59 mm in T2WI). We adopted 2 methods to predict CT coordinates with MR image sets: parallel translation and selective choice of axes according to phase-encoding direction. Both were equally effective at predicting CT coordinates using only MR; however, the latter may be easier to use in clinical settings. Acquiring MR in multiple phase-encoding directions and selecting axes according to the phase-encoding direction allows identification of more accurate coordinates for stereotactic procedures. © 2018 S. Karger AG, Basel.

Free energy from molecular dynamics with multiple constraints

NASA Astrophysics Data System (ADS)

den Otter, W. K.; Briels, W. J.

In molecular dynamics simulations of reacting systems, the key step to determining the equilibrium constant and the reaction rate is the calculation of the free energy as a function of the reaction coordinate. Intuitively the derivative of the free energy is equal to the average force needed to constrain the reaction coordinate to a constant value, but the metric tensor effect of the constraint on the sampled phase space distribution complicates this relation. The appropriately corrected expression for the potential of mean constraint force method (PMCF) for systems in which only the reaction coordinate is constrained was published recently. Here we will consider the general case of a system with multiple constraints. This situation arises when both the reaction coordinate and the 'hard' coordinates are constrained, and also in systems with several reaction coordinates. The obvious advantage of this method over the established thermodynamic integration and free energy perturbation methods is that it avoids the cumbersome introduction of a full set of generalized coordinates complementing the constrained coordinates. Simulations of n -butane and n -pentane in vacuum illustrate the method.

Neurotrophic factors as a therapeutic target for Parkinson's disease.

PubMed

Evans, Jonathan R; Barker, Roger A

2008-04-01

The search for therapeutic agents that might alter the disease course in Parkinson's disease (PD) is ongoing. One area of particular interest involves neurotrophic factors (NTFs), with those of the glial cell line-derived neurotrophic factor (GDNF) family showing greatest promise. The safety and efficacy of these therapies has recently come into question. Furthermore, many of the key questions pertaining to such therapies, such as the optimal method of delivery, timing of treatment and selection of patients most likely to benefit, remain unanswered. In this review we sought to evaluate the therapeutic potential of NTFs in the treatment of PD. We appraised the evidence provided by both in vitro and in vivo work before proceeding to a critical assessment of the relevant clinical trial data. Relevant literature was identified using a PubMed search of articles published up to October 2007. Search terms included: 'Parkinson's disease', 'Neurotrophic factors', 'BDNF' (Brain-derived neurotrophic factor), 'GDNF' and 'Neurturin'. Original articles were reviewed, and relevant citations from these articles were also appraised. NTF therapy has potential in the treatment of nigrostriatal dysfunction in PD but numerous methodological and safety issues will need to be addressed before this approach can be widely adopted. Furthermore PD is now recognized as being more than a pure motor disorder, and one in which neuronal loss is not just confined to the dopaminergic nigrostriatal system. Non-motor symptomatology in PD is unlikely to benefit from therapies that target only the nigrostriatal system, and this must inform our thinking as to the maximal achievable benefit that NTFs are ever likely to provide.

Brain-Derived Neurotrophic Factor Gene Expression in Pediatric Bipolar Disorder: Effects of Treatment and Clinical Response

ERIC Educational Resources Information Center

Pandey, Ghanshyam N.; Rizavi, Hooriyah S.; Dwivedi, Yogesh; Pavuluri, Mani N.

2008-01-01

The study determines the gene expression of brain-derived neurotrophic factor (BDNF) in the lymphocytes of subjects with pediatric bipolar disorder (PBD) before and during treatment with mood stabilizers and in drug-free normal control subjects. Results indicate the potential of BDNF levels as a biomarker for PBD and as a treatment predictor and…

Intraspinal Rewiring of the Corticospinal Tract Requires Target-Derived Brain-Derived Neurotrophic Factor and Compensates Lost Function after Brain Injury

ERIC Educational Resources Information Center

Ueno, Masaki; Hayano, Yasufumi; Nakagawa, Hiroshi; Yamashita, Toshihide

2012-01-01

Brain injury that results in an initial behavioural deficit is frequently followed by spontaneous recovery. The intrinsic mechanism of this functional recovery has never been fully understood. Here, we show that reorganization of the corticospinal tract induced by target-derived brain-derived neurotrophic factor is crucial for spontaneous recovery…

Engineered BDNF producing cells as a potential treatment for neurologic disease

PubMed Central

Deng, Peter; Anderson, Johnathon D.; Yu, Abigail S.; Annett, Geralyn; Fink, Kyle D.; Nolta, Jan A.

2018-01-01

Introduction Brain-derived neurotrophic factor (BDNF) has been implicated in wide range of neurological diseases and injury. This neurotrophic factor is vital for neuronal health, survival, and synaptic connectivity. Many therapies focus on the restoration or enhancement of BDNF following injury or disease progression. Areas covered The present review will focus on the mechanisms in which BDNF exerts its beneficial functioning, current BDNF therapies, issues and potential solutions for delivery of neurotrophic factors to the central nervous system, and other disease indications that may benefit from overexpression or restoration of BDNF. Expert opinion Due to the role of BDNF in neuronal development, maturation, and health, BDNF is implicated in numerous neurological diseases making it a prime therapeutic agent. Numerous studies have shown the therapeutic potential of BDNF in a number of neurodegenerative disease models and in acute CNS injury, however clinical translation has fallen short due to issues in delivering this molecule. The use of MSC as a delivery platform for BDNF holds great promise for clinical advancement of neurotrophic factor restoration. The ease with which MSC can be engineered opens the door to the possibility of using this cell-based delivery system to advance a BDNF therapy to the clinic. PMID:27159050

Brain-derived neurotrophic factor and its receptors in Bergmann glia cells.

PubMed

Poblete-Naredo, Irais; Guillem, Alain M; Juárez, Claudia; Zepeda, Rossana C; Ramírez, Leticia; Caba, Mario; Hernández-Kelly, Luisa C; Aguilera, José; López-Bayghen, Esther; Ortega, Arturo

2011-12-01

Brain-derived neurotrophic factor is an abundant and widely distributed neurotrophin expressed in the Central Nervous System. It is critically involved in neuronal differentiation and survival. The expression of brain-derived neurotrophic factor and that of its catalytic active cognate receptor (TrkB) has been extensively studied in neuronal cells but their expression and function in glial cells is still controversial. Despite of this fact, brain-derived neurotrophic factor is released from astrocytes upon glutamate stimulation. A suitable model to study glia/neuronal interactions, in the context of glutamatergic synapses, is the well-characterized culture of chick cerebellar Bergmann glia cells. Using, this system, we show here that BDNF and its functional receptor are present in Bergmann glia and that BDNF stimulation is linked to the activation of the phosphatidyl-inositol 3 kinase/protein kinase C/mitogen-activated protein kinase/Activator Protein-1 signaling pathway. Accordingly, reverse transcription-polymerase chain reaction (RT-PCR) experiments predicted the expression of full-length and truncated TrkB isoforms. Our results suggest that Bergmann glia cells are able to express and respond to BDNF stimulation favoring the notion of their pivotal role in neuroprotection. Copyright © 2011 Elsevier B.V. All rights reserved.

Protection by [6]-shogaol against lipopolysaccharide-induced toxicity in murine astrocytes is related to production of brain-derived neurotrophic factor.

PubMed

Shim, Sehwan; Kim, Sokho; Kwon, Young-Bae; Kwon, Jungkee

2012-03-01

[6]-Shogaol has beneficial effects in spinal neuronal regeneration, but associated molecules and mechanisms are not identified. Neurotrophic factors, including brain-derived neurotrophic factor (BDNF), are associated with proliferation and differentiation of neuronal cells and exert a neuroprotective effect in neurodegenerative models. We investigated whether treatment with [6]-shogaol increases BDNF expression in lipopolysaccharide (LPS)-treated astrocytes, and examined the effect of [6]-shogaol on neuronal protection. [6]-Shogaol significantly attenuated the cell death induced by LPS. Western blotting showed that [6]-shogaol treatment reduced Bax expression and increased B-cell lymphoma (Bcl)-2 and BclxL expression in LPS-treated cells, consistent with the effects of BDNF treatment. Furthermore, K252a, a blocker of neurotrophic factors, attenuated the cellular protective effects of [6]-shogaol and BDNF. This study provides the first evidence that [6]-shogaol increases the expression of BDNF in LPS-treated astrocytes. Furthermore, these experimental results indicate that production of BDNF in astrocytes might be related to altered cell viability following [6]-shogaol treatment. Thus, the neuroprotective effects of [6]-shogaol is mediated by up-regulation of BDNF. Copyright © 2011 Elsevier Ltd. All rights reserved.

Peptide profiling of Internet-obtained Cerebrolysin using high performance liquid chromatography - electrospray ionization ion trap and ultra high performance liquid chromatography - ion mobility - quadrupole time of flight mass spectrometry.

PubMed

Gevaert, Bert; D'Hondt, Matthias; Bracke, Nathalie; Yao, Han; Wynendaele, Evelien; Vissers, Johannes Petrus Cornelis; De Cecco, Martin; Claereboudt, Jan; De Spiegeleer, Bart

2015-09-01

Cerebrolysin, a parenteral peptide preparation produced by controlled digestion of porcine brain proteins, is an approved nootropic medicine in some countries. However, it is also easily and globally available on the Internet. Nevertheless, until now, its exact chemical composition was unknown. Using high performance liquid chromatography (HPLC) coupled to ion trap and ultra high performance liquid chromatography (UHPLC) coupled to quadrupole-ion mobility-time-of-flight mass spectrometry (Q-IM-TOF MS), combined with UniProt pig protein database search and PEAKS de novo sequencing, we identified 638 unique peptides in an Internet-obtained Cerebrolysin sample. The main components in this sample originate from tubulin alpha- and beta-chain, actin, and myelin basic protein. No fragments of known neurotrophic factors like glial cell-derived neurotrophic factor (GDNF), neurotrophin nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and ciliary neurotrophic factor (CNTF) were found, suggesting that the activities reported in the literature are likely the result of new, hitherto unknown cryptic peptides with nootropic properties. Copyright © 2015 John Wiley & Sons, Ltd.

A placebo-controlled trial of dextromethorphan as an adjunct in opioid-dependent patients undergoing methadone maintenance treatment.

PubMed

Lee, Sheng-Yu; Chen, Shiou-Lan; Chang, Yun-Hsuan; Chu, Chun-Hsien; Chen, Shih-Heng; Chen, Po See; Huang, San-Yuan; Tzeng, Nian-Sheng; Wang, Liang-Jen; Lee, I Hui; Wang, Tzu-Yun; Chen, Kao Chin; Yang, Yen Kuang; Hong, Jau-Shyong; Lu, Ru-Band

2015-02-25

Low-dose dextromethorphan (DM) might have anti-inflammatory and neurotrophic effects mechanistically remote from an NMDA receptor. In a randomized, double-blind, controlled 12 week study, we investigated whether add-on dextromethorphan reduced cytokine levels and benefitted opioid-dependent patients undergoing methadone maintenance therapy (MMT). Patients were randomly assigned to a group: DM60 (60mg/day dextromethorphan; n = 65), DM120 (120mg/day dextromethorphan; n = 65), or placebo (n = 66). Primary outcomes were the methadone dose required, plasma morphine level, and retention in treatment. Plasma tumor necrosis factor (TNF)-α, C-reactive protein, interleukin (IL)-6, IL-8, transforming growth factor-β1, and brain-derived neurotrophic factor (BDNF) levels were examined during weeks 0, 1, 4, 8, and 12. Multiple linear regressions with generalized estimating equation methods were used to examine the therapeutic effect. After 12 weeks, the DM60 group had significantly longer treatment retention and lower plasma morphine levels than did the placebo group. Plasma TNF-α was significantly decreased in the DM60 group compared to the placebo group. However, changes in plasma cytokine levels, BDNF levels, and the methadone dose required in the three groups were not significantly different. We provide evidence-decreased concomitant heroin use-of low-dose add-on DM's efficacy for treating opioid-dependent patients undergoing MMT. © The Author 2015. Published by Oxford University Press on behalf of CINP.

A Placebo-Controlled Trial of Dextromethorphan as an Adjunct in Opioid-Dependent Patients Undergoing Methadone Maintenance Treatment

PubMed Central

Lee, Sheng-Yu; Chen, Shiou-Lan; Chang, Yun-Hsuan; Chu, Chun-Hsien; Chen, Shih-Heng; Chen, Po See; Huang, San-Yuan; Tzeng, Nian-Sheng; Wang, Liang-Jen; Lee, I Hui; Wang, Tzu-Yun; Chen, Kao Chin; Yang, Yen Kuang; Hong, Jau-Shyong

2015-01-01

Background: Low-dose dextromethorphan (DM) might have anti-inflammatory and neurotrophic effects mechanistically remote from an NMDA receptor. In a randomized, double-blind, controlled 12 week study, we investigated whether add-on dextromethorphan reduced cytokine levels and benefitted opioid-dependent patients undergoing methadone maintenance therapy (MMT). Methods: Patients were randomly assigned to a group: DM60 (60mg/day dextromethorphan; n = 65), DM120 (120mg/day dextromethorphan; n = 65), or placebo (n = 66). Primary outcomes were the methadone dose required, plasma morphine level, and retention in treatment. Plasma tumor necrosis factor (TNF)-α, C-reactive protein, interleukin (IL)-6, IL-8, transforming growth factor–β1, and brain-derived neurotrophic factor (BDNF) levels were examined during weeks 0, 1, 4, 8, and 12. Multiple linear regressions with generalized estimating equation methods were used to examine the therapeutic effect. Results: After 12 weeks, the DM60 group had significantly longer treatment retention and lower plasma morphine levels than did the placebo group. Plasma TNF-α was significantly decreased in the DM60 group compared to the placebo group. However, changes in plasma cytokine levels, BDNF levels, and the methadone dose required in the three groups were not significantly different. Conclusions: We provide evidence—decreased concomitant heroin use—of low-dose add-on DM’s efficacy for treating opioid-dependent patients undergoing MMT. PMID:25716777

Up-regulation of Ciliary Neurotrophic Factor in Astrocytes by Aspirin

PubMed Central

Modi, Khushbu K.; Sendtner, Michael; Pahan, Kalipada

2013-01-01

Ciliary neurotrophic factor (CNTF) is a promyelinating trophic factor, and the mechanisms by which CNTF expression could be increased in the brain are poorly understood. Acetylsalicylic acid (aspirin) is one of the most widely used analgesics. Interestingly, aspirin increased mRNA and protein expression of CNTF in primary mouse and human astrocytes in a dose- and time-dependent manner. Aspirin induced the activation of protein kinase A (PKA) but not protein kinase C (PKC). H-89, an inhibitor of PKA, abrogated aspirin-induced expression of CNTF. The activation of cAMP-response element-binding protein (CREB), but not NF-κB, by aspirin, the abrogation of aspirin-induced expression of CNTF by siRNA knockdown of CREB, the presence of a consensus cAMP-response element in the promoter of CNTF, and the recruitment of CREB and CREB-binding protein to the CNTF promoter by aspirin suggest that aspirin increases the expression of the Cntf gene via the activation of CREB. Furthermore, we demonstrate that aspirin-induced astroglial CNTF was also functionally active and that supernatants of aspirin-treated astrocytes of wild type, but not Cntf null, mice increased myelin-associated proteins in oligodendrocytes and protected oligodendrocytes from TNF-α insult. These results highlight a new and novel myelinogenic property of aspirin, which may be of benefit for multiple sclerosis and other demyelinating disorders. PMID:23653362

Multiresource allocation and scheduling for periodic soft real-time applications

NASA Astrophysics Data System (ADS)

Gopalan, Kartik; Chiueh, Tzi-cker

2001-12-01

Real-time applications that utilize multiple system resources, such as CPU, disks, and network links, require coordinated scheduling of these resources in order to meet their end-to-end performance requirements. Most state-of-the-art operating systems support independent resource allocation and deadline-driven scheduling but lack coordination among multiple heterogeneous resources. This paper describes the design and implementation of an Integrated Real-time Resource Scheduler (IRS) that performs coordinated allocation and scheduling of multiple heterogeneous resources on the same machine for periodic soft real-time application. The principal feature of IRS is a heuristic multi-resource allocation algorithm that reserves multiple resources for real-time applications in a manner that can maximize the number of applications admitted into the system in the long run. At run-time, a global scheduler dispatches the tasks of the soft real-time application to individual resource schedulers according to the precedence constraints between tasks. The individual resource schedulers, which could be any deadline based schedulers, can make scheduling decisions locally and yet collectively satisfy a real-time application's performance requirements. The tightness of overall timing guarantees is ultimately determined by the properties of individual resource schedulers. However, IRS maximizes overall system resource utilization efficiency by coordinating deadline assignment across multiple tasks in a soft real-time application.

Plasticity in reflex pathways to the lower urinary tract following spinal cord injury

PubMed Central

de Groat, William C.; Yoshimura, Naoki

2013-01-01

The lower urinary tract has two main functions, storage and periodic expulsion of urine, that are regulated by a complex neural control system in the brain and lumbosacral spinal cord. This neural system coordinates the activity of two functional units in the lower urinary tract: (1) a reservoir (the urinary bladder) and (2) an outlet (consisting of bladder neck, urethra and striated muscles of the external urethra sphincter). During urine storage the outlet is closed and the bladder is quiescent to maintain a low intravesical pressure. During micturition the outlet relaxes and the bladder contracts to promote efficient release of urine. This reciprocal relationship between bladder and outlet is generated by reflex circuits some of which are under voluntary control. Experimental studies in animals indicate that the micturition reflex is mediated by a spinobulbospinal pathway passing through a coordination center (the pontine micturition center) located in the rostral brainstem. This reflex pathway is in turn modulated by higher centers in the cerebral cortex that are involved in the voluntary control of micturition. Spinal cord injury at cervical or thoracic levels disrupts voluntary control of voiding as well as the normal reflex pathways that coordinate bladder and sphincter function. Following spinal cord injury the bladder is initially areflexic but then becomes hyperreflexic due to the emergence of a spinal micturition reflex pathway. However the bladder does not empty efficiently because coordination between the bladder and urethral outlet is lost. Studies in animals indicate that dysfunction of the lower urinary tract after spinal cord injury is dependent in part on plasticity of bladder afferent pathways as well as reorganization of synaptic connections in the spinal cord. Reflex plasticity is associated with changes in the properties of ion channels and electrical excitability of afferent neurons and appears to be mediated in part by neurotrophic factors released in the spinal cord and/or the peripheral target organs. PMID:21596038

Integral Characterization of Defective BDNF/TrkB Signalling in Neurological and Psychiatric Disorders Leads the Way to New Therapies

PubMed Central

Tejeda, Gonzalo S.; Díaz-Guerra, Margarita

2017-01-01

Enhancement of brain-derived neurotrophic factor (BDNF) signalling has great potential in therapy for neurological and psychiatric disorders. This neurotrophin not only attenuates cell death but also promotes neuronal plasticity and function. However, an important challenge to this approach is the persistence of aberrant neurotrophic signalling due to a defective function of the BDNF high-affinity receptor, tropomyosin-related kinase B (TrkB), or downstream effectors. Such changes have been already described in several disorders, but their importance as pathological mechanisms has been frequently underestimated. This review highlights the relevance of an integrative characterization of aberrant BDNF/TrkB pathways for the rational design of therapies that by combining BDNF and TrkB targets could efficiently promote neurotrophic signalling. PMID:28134845

A Safe Cooperative Framework for Atmospheric Science Missions with Multiple Heterogeneous UAS using Piecewise Bezier Curves

NASA Technical Reports Server (NTRS)

Mehdi, S. Bilal; Puig-Navarro, Javier; Choe, Ronald; Cichella, Venanzio; Hovakimyan, Naira; Chandarana, Meghan; Trujillo, Anna; Rothhaar, Paul M.; Tran, Loc; Neilan, James H.;

Self-Healing Gelatin Hydrogels Cross-Linked by Combining Multiple Hydrogen Bonding and Ionic Coordination.

PubMed

Zhang, Guangzhao; Lv, Lei; Deng, Yonghong; Wang, Chaoyang

2017-06-01

Self-healing hydrogels have been studied by many researchers via multiple cross-linking approaches including physical and chemical interactions. It is an interesting project in multifunctional hydrogel exploration that a water soluble polymer matrix is cross-linked by combining the ionic coordination and the multiple hydrogen bonds to fabricate self-healing hydrogels with injectable property. This study introduces a general procedure of preparing the hydrogels (termed gelatin-UPy-Fe) cross-linked by both ionic coordination of Fe 3+ and carboxyl group from the gelatin and the quadruple hydrogen bonding interaction from the ureido-pyrimidinone (UPy) dimers. The gelatin-UPy-Fe hydrogels possess an excellent self-healing property. The effects of the ionic coordination of Fe 3+ and quadruple hydrogen bonding of UPy on the formation and mechanical behavior of the prepared hydrogels are investigated. In vitro drug release of the gelatin-UPy-Fe hydrogels is also observed, giving an intriguing glimpse into possible biological applications. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Coordinating Known and Unknown Quantities in a Multiplicative Context: Problem Conceptualization, Affordances and Constraints

ERIC Educational Resources Information Center

Ramful, Ajay

2012-01-01

In line with continuing efforts to explain the demanding nature of multiplicative reasoning among middle-school students, this study explores the fine-grained knowledge elements that two pairs of 7th and 8th graders deployed in their attempt to coordinate the known and unknown quantities in the gear-wheel problem. Failure to conceptualize the…

Telerobotic management system: coordinating multiple human operators with multiple robots

NASA Astrophysics Data System (ADS)

King, Jamie W.; Pretty, Raymond; Brothers, Brendan; Gosine, Raymond G.

2003-09-01

This paper describes an application called the Tele-robotic management system (TMS) for coordinating multiple operators with multiple robots for applications such as underground mining. TMS utilizes several graphical interfaces to allow the user to define a partially ordered plan for multiple robots. This plan is then converted to a Petri net for execution and monitoring. TMS uses a distributed framework to allow robots and operators to easily integrate with the applications. This framework allows robots and operators to join the network and advertise their capabilities through services. TMS then decides whether tasks should be dispatched to a robot or a remote operator based on the services offered by the robots and operators.

Automation of Coordinated Planning Between Observatories: The Visual Observation Layout Tool (VOLT)

NASA Technical Reports Server (NTRS)

Maks, Lori; Koratkar, Anuradha; Kerbel, Uri; Pell, Vince

2002-01-01

Fulfilling the promise of the era of great observatories, NASA now has more than three space-based astronomical telescopes operating in different wavebands. This situation provides astronomers with the unique opportunity of simultaneously observing a target in multiple wavebands with these observatories. Currently scheduling multiple observatories simultaneously, for coordinated observations, is highly inefficient. Coordinated observations require painstaking manual collaboration among the observatory staff at each observatory. Because they are time-consuming and expensive to schedule, observatories often limit the number of coordinated observations that can be conducted. In order to exploit new paradigms for observatory operation, the Advanced Architectures and Automation Branch of NASA's Goddard Space Flight Center has developed a tool called the Visual Observation Layout Tool (VOLT). The main objective of VOLT is to provide a visual tool to automate the planning of coordinated observations by multiple astronomical observatories. Four of NASA's space-based astronomical observatories - the Hubble Space Telescope (HST), Far Ultraviolet Spectroscopic Explorer (FUSE), Rossi X-ray Timing Explorer (RXTE) and Chandra - are enthusiastically pursuing the use of VOLT. This paper will focus on the purpose for developing VOLT, as well as the lessons learned during the infusion of VOLT into the planning and scheduling operations of these observatories.

EPO improved neurologic outcome in rat pups late after traumatic brain injury.

PubMed

Schober, Michelle E; Requena, Daniela F; Rodesch, Christopher K

2018-05-01

In adult rats, erythropoietin improved outcomes early and late after traumatic brain injury, associated with increased levels of Brain Derived Neurotrophic Factor. Using our model of pediatric traumatic brain injury, controlled cortical impact in 17-day old rats, we previously showed that erythropoietin increased hippocampal neuronal fraction in the first two days after injury. Erythropoietin also decreased activation of caspase3, an apoptotic enzyme modulated by Brain Derived Neurotrophic Factor, and improved Novel Object Recognition testing 14 days after injury. Data on long-term effects of erythropoietin on Brain Derived Neurotrophic Factor expression, histology and cognitive function after developmental traumatic brain injury are lacking. We hypothesized that erythropoietin would increase Brain Derived Neurotrophic Factor and improve long-term object recognition in rat pups after controlled cortical impact, associated with increased neuronal fraction in the hippocampus. Rats pups received erythropoietin or vehicle at 1, 24, and 48 h and 7 days after injury or sham surgery followed by histology at 35 days, Novel Object Recognition testing at adulthood, and Brain Derived Neurotrophic Factor measurements early and late after injury. Erythropoietin improved Novel Object Recognition performance and preserved hippocampal volume, but not neuronal fraction, late after injury. Improved object recognition in erythropoietin treated rats was associated with preserved hippocampal volume late after traumatic brain injury. Erythropoietin is approved to treat various pediatric conditions. Coupled with exciting experimental and clinical studies suggesting it is beneficial after neonatal hypoxic ischemic brain injury, our preliminary findings support further study of erythropoietin use after developmental traumatic brain injury. Copyright © 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Prenatal and Early Postnatal Exposure to Cigarette Smoke Decreases BDNF/TrkB Signaling and Increases Abnormal Behaviors Later in Life

PubMed Central

Xiao, Lan; Kish, Vincent L.; Benders, Katherine M.

2016-01-01

Background: Cigarette smoke exposure during prenatal and early postnatal periods increases the incidence of a variety of abnormal behaviors later in life. The purpose of this study was to identify the possible critical period of susceptibility to cigarette smoke exposure and evaluate the possibe effects of cigarette smoke during early life on brain-derived neurotrophic factor/neurotrophic tyrosine kinase receptor B signaling in the brain. Methods: Three different age of imprinting control region mice were exposed to cigarette smoke or filtered air for 10 consecutive days beginning on either gestational day 7 by maternal exposure, or postnatal days 2 or 21 by direct inhalation. A series of behavioral profiles and neurotrophins in brain were measured 24 hours after mice received acute restraint stress for 1 hour on postnatal day 59. Results: Cigarette smoke exposure in gestational day 7 and postnatal day 2 produced depression-like behaviors as evidenced by significantly increased immobility in both tail suspension and forced-swim test. Increased entry latencies, but not ambulation in the open field test, were also observed in the gestational day 7 and postnatal day 2 cigarette smoke exposure groups. Genetic analysis showed that gestational day 7 cigarette smoke exposure significantly altered mRNA level of brain-derived neurotrophic factor/tyrosine kinase receptor B in the hippocampus. However, behavioral profiles and brain-derived neurotrophic factor/tyrosine kinase receptor B signaling were not significantly changed in PND21 cigarette smoke exposure group compared with FA group. Conclusions: These results suggest that a critical period of susceptibility to cigarette smoke exposure exists in the prenatal and early postnatal period, which results a downregulation in brain-derived neurotrophic factor/tyrosine kinase receptor B signaling in the hippocampus and enhances depression-like behaviors later in life. PMID:26503133

Mitochondria Are Critical for BDNF-Mediated Synaptic and Vascular Plasticity of Hippocampus following Repeated Electroconvulsive Seizures.

PubMed

Chen, Fenghua; Ardalan, Maryam; Elfving, Betina; Wegener, Gregers; Madsen, Torsten M; Nyengaard, Jens R

2018-03-01

Electroconvulsive therapy is a fast-acting and efficient treatment of depression used in the clinic. The underlying mechanism of its therapeutic effect is still unclear. However, recovery of synaptic connections and synaptic remodeling is thought to play a critical role for the clinical efficacy obtained from a rapid antidepressant response. Here, we investigated the relationship between synaptic changes and concomitant nonneuronal changes in microvasculature and mitochondria and its relationship to brain-derived neurotrophic factor level changes after repeated electroconvulsive seizures, an animal model of electroconvulsive therapy. Electroconvulsive seizures or sham treatment was given daily for 10 days to rats displaying a genetically driven phenotype modelling clinical depression: the Flinders Sensitive and Resistant Line rats. Stereological principles were employed to quantify numbers of synapses and mitochondria, and the length of microvessels in the hippocampus. The brain-derived neurotrophic factor protein levels were quantified with immunohistochemistry. In untreated controls, a lower number of synapses and mitochondria was accompanied by shorter microvessels of the hippocampus in "depressive" phenotype (Flinders Sensitive Line) compared with the "nondepressed" phenotype (Flinders Resistant Line). Electroconvulsive seizure administration significantly increased the number of synapses and mitochondria, and length of microvessels both in Flinders Sensitive Line-electroconvulsive seizures and Flinders Resistant Line-electroconvulsive seizures rats. In addition, the amount of brain-derived neurotrophic factor protein was significantly increased in Flinders Sensitive Line and Flinders Resistant Line rats after electroconvulsive seizures. Furthermore, there was a significant positive correlation between brain-derived neurotrophic factor level and mitochondria/synapses. Our results indicate that rapid and efficient therapeutic effect of electroconvulsive seizures may be related to synaptic plasticity, accompanied by brain-derived neurotrophic factor protein level elevation and mitochondrial and vascular support. © The Author(s) 2017. Published by Oxford University Press on behalf of CINP.

Dendrobium alkaloids prevent Aβ25–35-induced neuronal and synaptic loss via promoting neurotrophic factors expression in mice

PubMed Central

Nie, Jing; Tian, Yong; Zhang, Yu; Lu, Yan-Liu; Li, Li-Sheng

2016-01-01

Background Neuronal and synaptic loss is the most important risk factor for cognitive impairment. Inhibiting neuronal apoptosis and preventing synaptic loss are promising therapeutic approaches for Alzheimer’s disease (AD). In this study, we investigate the protective effects of Dendrobium alkaloids (DNLA), a Chinese medicinal herb extract, on β-amyloid peptide segment 25–35 (Aβ25-35)-induced neuron and synaptic loss in mice. Method Aβ25–35(10 µg) was injected into the bilateral ventricles of male mice followed by an oral administration of DNLA (40 mg/kg) for 19 days. The Morris water maze was used for evaluating the ability of spatial learning and memory function of mice. The morphological changes were examined via H&E staining and Nissl staining. TUNEL staining was used to check the neuronal apoptosis. The ultrastructure changes of neurons were observed under electron microscope. Western blot was used to evaluate the protein expression levels of ciliary neurotrophic factor (CNTF), glial cell line-derived neurotrophic factor (GDNF), and brain-derived neurotrophic factor (BDNF) in the hippocampus and cortex. Results DNLA significantly attenuated Aβ25–35-induced spatial learning and memory impairments in mice. DNLA prevented Aβ25–35-induced neuronal loss in the hippocampus and cortex, increased the number of Nissl bodies, improved the ultrastructural injury of neurons and increased the number of synapses in neurons. Furthermore, DNLA increased the protein expression of neurotrophic factors BDNF, CNTF and GDNF in the hippocampus and cortex. Conclusions DNLA can prevent neuronal apoptosis and synaptic loss. This effect is mediated at least in part via increasing the expression of BDNF, GDNF and CNTF in the hippocampus and cortex; improving Aβ-induced spatial learning and memory impairment in mice. PMID:27994964

The canonical nuclear factor-κB pathway regulates cell survival in a developmental model of spinal cord motoneurons.

PubMed

Mincheva, Stefka; Garcera, Ana; Gou-Fabregas, Myriam; Encinas, Mario; Dolcet, Xavier; Soler, Rosa M

2011-04-27

In vivo and in vitro motoneuron survival depends on the support of neurotrophic factors. These factors activate signaling pathways related to cell survival or inactivate proteins involved in neuronal death. In the present work, we analyzed the involvement of the nuclear factor-κB (NF-κB) pathway in mediating mouse spinal cord motoneuron survival promoted by neurotrophic factors. This pathway comprises ubiquitously expressed transcription factors that could be activated by two different routes: the canonical pathway, associated with IKKα/IKKβ kinase phosphorylation and nuclear translocation RelA (p65)/p50 transcription factors; and the noncanonical pathway, related to IKKα kinase homodimer phosphorylation and RelB/p52 transcription factor activation. In our system, we show that neurotrophic factors treatment induced IKKα and IKKβ phosphorylation and RelA nuclear translocation, suggesting NF-κB pathway activation. Protein levels of different members of the canonical or noncanonical pathways were reduced in a primary culture of isolated embryonic motoneurons using an interference RNA approach. Even in the presence of neurotrophic factors, selective reduction of IKKα, IKKβ, or RelA proteins induced cell death. In contrast, RelB protein reduction did not have a negative effect on motoneuron survival. Together these results demonstrated that the canonical NF-κB pathway mediates motoneuron survival induced by neurotrophic factors, and the noncanonical pathway is not related to this survival effect. Canonical NF-κB blockade induced an increase of Bim protein level and apoptotic cell death. Bcl-x(L) overexpression or Bax reduction counteracted this apoptotic effect. Finally, RelA knockdown causes changes of CREB and Smn protein levels.

Norrin mediates neuroprotective effects on retinal ganglion cells via activation of the Wnt/beta-catenin signaling pathway and the induction of neuroprotective growth factors in Muller cells.

PubMed

Seitz, Roswitha; Hackl, Simon; Seibuchner, Thomas; Tamm, Ernst R; Ohlmann, Andreas

2010-04-28

Norrin is a secreted protein that binds to frizzled 4 and controls development of capillaries in retina and inner ear. We provide evidence that Norrin has distinct neuroprotective properties that are independent from its effects on vascular development. The function of Norrin was investigated in a mouse model of excitotoxic retinal ganglion cell (RGC) damage after intravitreal injection of NMDA, and in cultured Müller glia or immortalized RGC-5 cells. Intravitreal injection of Norrin significantly increased the number of surviving RGC axons in the optic nerve and decreased apoptotic death of retinal neurons following NMDA-mediated damage. This effect could be blocked by adding dickkopf (DKK)-1, an inhibitor of the Wnt/beta-catenin signaling pathway. Treatment of eyes with combined Norrin/NMDA activated Wnt/beta-catenin signaling and increased the retinal expression of leukemia inhibitory factor and endothelin-2, as well as that of neurotrophic growth factors such as fibroblast growth factor-2, brain-derived neurotrophic factor, lens epithelium-derived growth factor, and ciliary neurotrophic factor. A similar activation of Wnt/beta-catenin signaling and an increased expression of neurotrophic factors was observed in cultured Müller cells after treatment with Norrin, effects that again could be blocked by adding DKK-1. In addition, conditioned cell culture medium of Norrin-treated Müller cells increased survival of differentiated RGC-5 cells. We conclude that Norrin has pronounced neuroprotective properties on retinal neurons with the distinct potential to decrease the damaging effects of NMDA-induced RGC loss. The effects of Norrin involve activation of Wnt/beta-catenin signaling and subsequent induction of neurotrophic growth factors in Müller cells.

Z-Guggulsterone Produces Antidepressant-Like Effects in Mice through Activation of the BDNF Signaling Pathway

PubMed Central

Liu, Feng-Guo; Hu, Wen-Feng; Wang, Ji-Li; Wang, Peng; Gong, Yu; Tong, Li-Juan; Jiang, Bo; Zhang, Wei; Qin, Yi-Bin; Chen, Zhuo

2017-01-01

Abstract Background: Z-guggulsterone, an active compound extracted from the gum resin of the tree Commiphora mukul, has been shown to improve animal memory deficits via activating the brain-derived neurotrophic factor signaling pathway. Here, we investigated the antidepressant-like effect of Z-guggulsterone in a chronic unpredictable stress mouse model of depression. Methods: The effects of Z-guggulsterone were assessed in mice with the tail suspension test and forced swimming test. Z-guggulsterone was also investigated in the chronic unpredictable stress model of depression with fluoxetine as the positive control. Changes in hippocampal neurogenesis as well as the brain-derived neurotrophic factor signaling pathway after chronic unpredictable stress/Z-guggulsterone treatment were investigated. The tryptophan hydroxylase inhibitor and the tyrosine kinase B inhibitor were also used to explore the antidepressant-like mechanisms of Z-guggulsterone. Results: Z-guggulsterone (10, 30 mg/kg) administration protected the mice against the chronic unpredictable stress-induced increases in the immobile time in the tail suspension test and forced swimming test and also reversed the reduction in sucrose intake in sucrose preference experiment. Z-guggulsterone (10, 30 mg/kg) administration prevented the reductions in brain-derived neurotrophic factor protein expression levels as well as the phosphorylation levels of cAMP response element binding protein, extracellular signal-regulated kinase 1/2, and protein kinase B in the hippocampus and cortex induced by chronic unpredictable stress. Z-guggulsterone (10, 30 mg/kg) treatment also improved hippocampal neurogenesis in chronic unpredictable stress-treated mice. Blockade of the brain-derived neurotrophic factor signal, but not the monoaminergic system, attenuated the antidepressant-like effects of Z-guggulsterone. Conclusions: Z-guggulsterone exhibits antidepressant activity via activation of the brain-derived neurotrophic factor signaling pathway and upregulation of hippocampal neurogenesis. PMID:28339691

Differential effects of voluntary wheel running and toy rotation on the mRNA expression of neurotrophic factors and FKBP5 in a post-traumatic stress disorder rat model with the shuttle-box task.

PubMed

Tanichi, Masaaki; Toda, Hiroyuki; Shimizu, Kunio; Koga, Minori; Saito, Taku; Enomoto, Shingo; Boku, Shuken; Asai, Fumiho; Mitsui, Yumi; Nagamine, Masanori; Fujita, Masanori; Yoshino, Aihide

2018-06-18

Life-threatening experiences can result in the development of post-traumatic stress disorder. We have developed an animal model for post-traumatic stress disorder (PTSD) using a shuttle box in rats. In this paradigm, the rats were exposed to inescapable foot-shock stress (IS) in a shuttle box, and then an avoidance/escape task was performed in the same box 2 weeks after IS. A previous study using this paradigm revealed that environmental enrichment (EE) ameliorated avoidance/numbing-like behaviors, but not hyperarousal-like behaviors, and EE also elevated hippocampal brain-derived neurotrophic factor (BDNF) expression. However, the differential effects of EE components, i.e., running wheel (RW) or toy rotation, on PTSD-like behaviors has remained unclear. In this experiment, we demonstrated that RW, toy rotation, and EE (containing RW and toy rotation) ameliorated avoidance/numbing-like behaviors, induced learning of avoidance responses, and improved depressive-like behaviors in traumatized rats. The RW increased the hippocampal mRNA expression of neurotrophic factors, especially BDNF and glial-cell derived neurotrophic factor. Toy rotation influenced FK506 binding protein 5 mRNA expression, which is believed to be a regulator of the hypothalamic-pituitary-adrenal (HPA)-axis system, in the hippocampus and amygdala. This is the first report to elucidate the differential mechanistic effects of RW and toy rotation. The former appears to exert its effects via neurotrophic factors, while the latter exerts its effects via the HPA axis. Further studies will lead to a better understanding of the influence of environmental factors on PTSD. Copyright © 2018 Elsevier Inc. All rights reserved.

Oligodendrocyte ablation affects the coordinated interaction between granule and Purkinje neurons during cerebellum development

DOE Office of Scientific and Technical Information (OSTI.GOV)

Collin, Ludovic; Doretto, Sandrine; Department of Psychiatry and Human Behavior, University of California Irvine, 3226 Gillespie Neuroscience Research Facility, Irvine CA 92697

2007-08-01

Oligodendrocytes (OLs) are the glial cells of the central nervous system (CNS) classically known to be devoted to the formation of myelin sheaths around most axons of the vertebrate brain. We have addressed the role of these cells during cerebellar development, by ablating OLs in vivo. Previous analyses had indicated that OL ablation during the first six postnatal days results into a striking cerebellar phenotype, whose major features are a strong reduction of granule neurons and aberrant Purkinje cells development. These two cell types are highly interconnected during cerebellar development through the production of molecules that help their proliferation, differentiationmore » and maintenance. In this article, we present data showing that OL ablation has major effects on the physiology of Purkinje (PC) and granule cells (GC). In particular, OL ablation results into a reduction of sonic hedgehog (Shh), Brain Derived Neurotrophic Factor (BDNF), and Reelin (Rln) expression. These results indicate that absence of OLs profoundly alters the normal cerebellar developmental program.« less

CYFIP1 Coordinates mRNA Translation and Cytoskeleton Remodeling to Ensure Proper Dendritic Spine Formation

PubMed Central

De Rubeis, Silvia; Pasciuto, Emanuela; Li, Ka Wan; Fernández, Esperanza; Di Marino, Daniele; Buzzi, Andrea; Ostroff, Linnaea E.; Klann, Eric; Zwartkruis, Fried J.T.; Komiyama, Noboru H.; Grant, Seth G.N.; Poujol, Christel; Choquet, Daniel; Achsel, Tilmann; Posthuma, Danielle; Smit, August B.; Bagni, Claudia

2013-01-01

Summary The CYFIP1/SRA1 gene is located in a chromosomal region linked to various neurological disorders, including intellectual disability, autism, and schizophrenia. CYFIP1 plays a dual role in two apparently unrelated processes, inhibiting local protein synthesis and favoring actin remodeling. Here, we show that brain-derived neurotrophic factor (BDNF)-driven synaptic signaling releases CYFIP1 from the translational inhibitory complex, triggering translation of target mRNAs and shifting CYFIP1 into the WAVE regulatory complex. Active Rac1 alters the CYFIP1 conformation, as demonstrated by intramolecular FRET, and is key in changing the equilibrium of the two complexes. CYFIP1 thus orchestrates the two molecular cascades, protein translation and actin polymerization, each of which is necessary for correct spine morphology in neurons. The CYFIP1 interactome reveals many interactors associated with brain disorders, opening new perspectives to define regulatory pathways shared by neurological disabilities characterized by spine dysmorphogenesis. PMID:24050404

Neurotrophic and Neurotoxic Effects of Amyloid |beta Protein: Reversal by Tachykinin Neuropeptides

NASA Astrophysics Data System (ADS)

Yankner, Bruce A.; Duffy, Lawrence K.; Kirschner, Daniel A.

1990-10-01

The amyloid β protein is deposited in the brains of patients with Alzheimer's disease but its pathogenic role is unknown. In culture, the amyloid β protein was neurotrophic to undifferentiated hippocampal neurons at low concentrations and neurotoxic to mature neurons at higher concentrations. In differentiated neurons, amyloid β protein caused dendritic and axonal retraction followed by neuronal death. A portion of the amyloid β protein (amino acids 25 to 35) mediated both the trophic and toxic effects and was homologous to the tachykinin neuropeptide family. The effects of the amyloid β protein were mimicked by tachykinin antagonists and completely reversed by specific tachykinin agonists. Thus, the amyloid β protein could function as a neurotrophic factor for differentiating neurons, but at high concentrations in mature neurons, as in Alzheimer's disease, could cause neuronal degeneration.

Autologous epidermal cells can induce wound closure of neurotrophic ulceration caused by trigeminal trophic syndrome.

PubMed

Schwerdtner, O; Damaskos, T; Kage, A; Weitzel-Kage, D; Klein, M

2005-06-01

Trigeminal trophic syndrome is an extremely rare complication following surgical ablation of the trigeminal nerve or after alcohol injection or thermocoagulation of the Gasserian ganglion. These lesions show a poor healing tendency and sometimes persist for years. The therapeutic results of local wound care with ointments and wound dressings are often unsatisfactory, and those of plastic surgery are variable. In the case presented, the skin area affected by neurotrophic ulceration is successfully treated with autologous cultivated epidermal cells. This form of tissue engineering is already a clinically established procedure for treating burns and chronic wounds. The results show for the first time that transplantation of in vitro cultivated epidermal cells can induce tissue regeneration and may be an effective tool in the treatment of neurotrophic ulcerations in the facial region.

Multiple Sensory-Motor Pathways Lead to Coordinated Visual Attention

PubMed Central

Yu, Chen; Smith, Linda B.

2016-01-01

Joint attention has been extensively studied in the developmental literature because of overwhelming evidence that the ability to socially coordinate visual attention to an object is essential to healthy developmental outcomes, including language learning. The goal of the present study is to understand the complex system of sensory-motor behaviors that may underlie the establishment of joint attention between parents and toddlers. In an experimental task, parents and toddlers played together with multiple toys. We objectively measured joint attention – and the sensory-motor behaviors that underlie it – using a dual head-mounted eye-tracking system and frame-by-frame coding of manual actions. By tracking the momentary visual fixations and hand actions of each participant, we precisely determined just how often they fixated on the same object at the same time, the visual behaviors that preceded joint attention, and manual behaviors that preceded and co-occurred with joint attention. We found that multiple sequential sensory-motor patterns lead to joint attention. In addition, there are developmental changes in this multi-pathway system evidenced as variations in strength among multiple routes. We propose that coordinated visual attention between parents and toddlers is primarily a sensory-motor behavior. Skill in achieving coordinated visual attention in social settings – like skills in other sensory-motor domains – emerges from multiple pathways to the same functional end. PMID:27016038

Multiple Sensory-Motor Pathways Lead to Coordinated Visual Attention.

PubMed

Yu, Chen; Smith, Linda B

2017-02-01

Joint attention has been extensively studied in the developmental literature because of overwhelming evidence that the ability to socially coordinate visual attention to an object is essential to healthy developmental outcomes, including language learning. The goal of this study was to understand the complex system of sensory-motor behaviors that may underlie the establishment of joint attention between parents and toddlers. In an experimental task, parents and toddlers played together with multiple toys. We objectively measured joint attention-and the sensory-motor behaviors that underlie it-using a dual head-mounted eye-tracking system and frame-by-frame coding of manual actions. By tracking the momentary visual fixations and hand actions of each participant, we precisely determined just how often they fixated on the same object at the same time, the visual behaviors that preceded joint attention and manual behaviors that preceded and co-occurred with joint attention. We found that multiple sequential sensory-motor patterns lead to joint attention. In addition, there are developmental changes in this multi-pathway system evidenced as variations in strength among multiple routes. We propose that coordinated visual attention between parents and toddlers is primarily a sensory-motor behavior. Skill in achieving coordinated visual attention in social settings-like skills in other sensory-motor domains-emerges from multiple pathways to the same functional end. Copyright © 2016 Cognitive Science Society, Inc.

Astrocytes mediated the nootropic and neurotrophic effects of Sarsasapogenin-AA13 via upregulating brain-derived neurotrophic factor.

PubMed

Dong, Dong; Mao, Yu; Huang, Cui; Jiao, Qian; Pan, Hui; Ma, Lei; Wang, Rui

2017-01-01

Rhizoma Anemarrhena , a widely used traditional Chinese medicine, has previously been shown to have neuroprotective effect. Sarsasapogenin-AA13 (AA13) is a novel synthetic derivative of Sarsasapogenin, which is extracted from Rhizoma Anemarrhena . The aim of this study is to investigate the nootropic and neurotrophic effects of AA13 and underlying mechanisms. In vitro , cell viability of rat primary astrocytes treated with AA13 and neurons cultured with conditioned medium of AA13-treated rat primary astrocytes was tested by MTT assays. In vivo , a pharmacological model of cognitive impairment induced by scopolamine was employed and spatial memory of the mice was assessed by Morris water maze. This study found that AA13 increased cell viability of primary astrocytes and AA13-treated astrocyte-conditioned medium enhanced the survival rate of primary neurons. Interestingly, AA13 markedly enhanced the level of BDNF in astrocytes. Furthermore, AA13 (6 mg/kg) improved the cognitive deficits in animal models (p<0.05) and BDNF and PSD95 levels were increased in brain. Therefore, we hypothesize that AA13 exerts nootropic and neurotrophic activities through astrocytes mediated upregulation of BDNF secretion. The results suggest that AA13 could be a potential compound for cognitive impairment after further research.

Inflammatory mediators of cognitive impairment in bipolar disorder

PubMed Central

Bauer, Isabelle E.; Pascoe, Michaela C.; Wollenhaupt-Aguiar, Bianca; Kapczinski, Flavio; Soares, Jair C.

2014-01-01

Objectives Recent studies have pointed to neuroinflammation, oxidative stress and neurotrophic factors as key mediators in the pathophysiology of mood disorders. Little is however known about the cascade of biological episodes underlying the cognitive deficits observed during the acute and euthymic phases of bipolar disorder (BD). The aim of this review is to assess the potential association between cognitive impairment and biomarkers of inflammation, oxidative stress and neurotrophic activity in BD. Methods Scopus (all databases), Pubmed and Ovid Medline were systematically searched with no language or year restrictions, up to November 2013, for human studies that collected both inflammatory markers and cognitive data in BD. Selected search terms were bipolar disorder, depression, mania, psychosis, inflammatory, cognitive and neurotrophic. Results Ten human studies satisfied the criteria for consideration. The findings showed that high levels of peripheral inflammatory-cytokine, oxidative stress and reduced brain derived neurotrophic factor (BDNF) levels were associated with poor cognitive performance. The BDNF val66met polymorphism is a potential vulnerability factor for cognitive impairment in BD. Conclusions Current data provide preliminary evidence of a link between the cognitive decline observed in BD and mechanisms of neuroinflammation and neuroprotection. The identification of BD specific inflammatory markers and polymorphisms in inflammatory response genes may be of assistance for therapeutic intervention. PMID:24862657

Association of Genetic Variants in the Neurotrophic Receptor–Encoding Gene NTRK2 and a Lifetime History of Suicide Attempts in Depressed Patients

PubMed Central

Kohli, Martin A.; Salyakina, Daria; Pfennig, Andrea; Lucae, Susanne; Horstmann, Sonja; Menke, Andreas; Kloiber, Stefan; Hennings, Johannes; Bradley, Bekh B.; Ressler, Kerry J.; Uhr, Manfred; Müller-Myhsok, Bertram; Holsboer, Florian; Binder, Elisabeth B.

2013-01-01

Context A consistent body of evidence supports a role of reduced neurotrophic signaling in the pathophysiology of major depressive disorder (MDD) and suicidal behavior. Especially in suicide victims, lower postmortem brain messenger RNA and protein levels of neurotrophins and their receptors have been reported. Objective To determine whether the brain-derived neurotrophic factor (BDNF) gene or its high-affinity receptor gene, receptor tyrosine kinase 2 (NTRK2), confer risk for suicide attempt (SA) and MDD by investigating common genetic variants in these loci. Design Eighty-three tagging single-nucleotide polymorphisms (SNPs) covering the genetic variability of these loci in European populations were assessed in a casecontrol association design. Setting Inpatients and screened control subjects. Participants The discovery sample consisted of 394 depressed patients, of whom 113 had SA, and 366 matched healthy control subjects. The replication studies comprised 744 German patients with MDD and 921 African American nonpsychiatric clinic patients, of whom 152 and 119 were positive for SA, respectively. Interventions Blood or saliva samples were collected from each participant for DNA extraction and genotyping. Main Outcome Measures Associations of SNPs in BDNF and NTRK2 with SA and MDD. Results Independent SNPs within NTRK2 were associated with SA among depressed patients of the discovery sample that could be confirmed in both the German and African American replication samples. Multilocus interaction analysis revealed that single SNP associations within this locus contribute to the risk of SA in a multiplicative and interactive fashion (P = 4.7× 10−7 for a 3-SNP model in the combined German sample). The effect size was 4.5 (95% confidence interval, 2.1–9.8) when patients carrying risk genotypes in all 3 markers were compared with those without any of the 3 risk genotypes. Conclusions Our results suggest that a combination of several independent risk alleles within the NTRK2 locus is associated with SA in depressed patients, further supporting a role of neurotrophins in the pathophysiology of suicide. PMID:20124106

Socioeconomic Disadvantage Moderates the Association between Peripheral Biomarkers and Childhood Psychopathology

PubMed Central

Mansur, Rodrigo B.; Cunha, Graccielle R.; Asevedo, Elson; Zugman, André; Zeni-Graiff, Maiara; Rios, Adiel C.; Sethi, Sumit; Maurya, Pawan K.; Levandowski, Mateus L.; Gadelha, Ary; Pan, Pedro M.; Stertz, Laura; Belangero, Síntia I.; Kauer-Sant' Anna, Márcia; Teixeira, Antônio L.; Mari, Jair J.; Rohde, Luis A.; Miguel, Euripedes C.; McIntyre, Roger S.; Grassi-Oliveira, Rodrigo; Bressan, Rodrigo A.; Brietzke, Elisa

2016-01-01

Background Socioeconomic disadvantage (SED) has been consistently associated with early life mental health problems. SED has been shown to impact multiple biological systems, including the regulation of neurotrophic proteins, immune-inflammatory and oxidative stress markers, which, conversely, have been reported to be relevant to physiological and pathological neurodevelopment This study investigated the relationship between SED, different domains of psychopathology, serum levels of interleukin-6 (IL6), thiobarbituric acid-reactive substance (TBARS) and brain-derived neurotrophic factor (BDNF). We hypothesized that a composite of socioeconomic risk would be associated with psychopathology and altered levels of peripheral biomarkers. In addition, we hypothesized that SED would moderate the associations between mental health problems, IL6, TBARS and BDNF. Methods and Findings Using a cross-sectional design, we measured the serum levels of IL6, TBARS and BDNF in 495 children aged 6 to 12. We also investigated socio-demographic characteristics and mental health problems using the Child Behaviour Checklist (CBCL) DSM-oriented scales. SED was evaluated using a cumulative risk model. Generalized linear models were used to assess associations between SED, biomarkers levels and psychopathology. SED was significantly associated with serum levels of IL6 (RR = 1.026, 95% CI 1.004; 1.049, p = 0.020) and TBARS (RR = 1.077, 95% CI 1.028; 1.127, p = 0.002). The association between SED and BDNF was not statistically significant (RR = 1.031, 95% CI 0.997; 1.066, p = 0.077). SED was also significantly associated with all CBCL DSM-oriented scales (all p < 0.05), whereas serum biomarkers (i.e. IL6, TBARS, BDNF) were associated with specific subscales. Moreover, the associations between serum biomarkers and domains of psychopathology were moderated by SED, with stronger correlations between mental health problems, IL6, TBARS, and BDNF being observed in children with high SED. Conclusions In children, SED is highly associated with mental health problems. Our findings suggest that this association may be moderated via effects on multiple interacting neurobiological systems. PMID:27489945

Amygdala Volume in Offspring from Multiplex for Alcohol Dependence Families: The Moderating Influence of Childhood Environment and 5-HTTLPR Variation.

PubMed

Hill, Shirley Y; Wang, Shuhui; Carter, Howard; McDermott, Michael D; Zezza, Nicholas; Stiffler, Scott

2013-12-12

The increased susceptibility for developing alcohol dependence seen in offspring from families with alcohol dependence may be related to structural and functional differences in brain circuits that influence emotional processing. Early childhood environment, genetic variation in the serotonin transporter-linked polymorphic region (5-HTTLPR) of the SLCA4 gene and allelic variation in the Brain Derived Neurotrophic Factor (BDNF) gene have each been reported to be related to volumetric differences in the temporal lobe especially the amygdala. Magnetic resonance imaging was used to obtain amygdala volumes for 129 adolescent/young adult individuals who were either High-Risk (HR) offspring from families with multiple cases of alcohol dependence (N=71) or Low-Risk (LR) controls (N=58). Childhood family environment was measured prospectively using age-appropriate versions of the Family Environment Scale during a longitudinal follow-up study. The subjects were genotyped for Brain-Derived Neurotrophic Factor (BDNF) Val66Met and the serotonin transporter polymorphism (5-HTTLPR). Two family environment scale scores (Cohesion and Conflict), genotypic variation, and their interaction were tested for their association with amygdala volumes. Personal and prenatal exposure to alcohol and drugs were considered in statistical analyses in order to more accurately determine the effects of familial risk group differences. Amygdala volume was reduced in offspring from families with multiple alcohol dependent members in comparison to offspring from control families. High-Risk offspring who were carriers of the S variant of the 5-HTTLPR polymorphism had reduced amygdala volume in comparison to those with an LL genotype. Larger amygdala volume was associated with greater family cohesion but only in Low-Risk control offspring. Familial risk for alcohol dependence is an important predictor of amygdala volume even when removing cases with significant personal exposure and covarying for prenatal exposure effects. The present study provides new evidence that amygdala volume is modified by 5-HTTLPR variation in High-Risk families.

Deadlines in space: Selective effects of coordinate spatial processing in multitasking.

PubMed

Todorov, Ivo; Del Missier, Fabio; Konke, Linn Andersson; Mäntylä, Timo

2015-11-01

Many everyday activities require coordination and monitoring of multiple deadlines. One way to handle these temporal demands might be to represent future goals and deadlines as a pattern of spatial relations. We examined the hypothesis that spatial ability, in addition to executive functioning, contributes to individual differences in multitasking. In two studies, participants completed a multitasking session in which they monitored four digital clocks running at different rates. In Study 1, we found that individual differences in spatial ability and executive functions were independent predictors of multiple-task performance. In Study 2, we found that individual differences in specific spatial abilities were selectively related to multiple-task performance, as only coordinate spatial processing, but not categorical, predicted multitasking, even beyond executive functioning and numeracy. In both studies, males outperformed females in spatial ability and multitasking and in Study 2 these sex differences generalized to a simulation of everyday multitasking. Menstrual changes moderated the effects on multitasking, in that sex differences in coordinate spatial processing and multitasking were observed between males and females in the luteal phase of the menstrual cycle, but not between males and females at menses. Overall, these findings suggest that multiple-task performance reflects independent contributions of spatial ability and executive functioning. Furthermore, our results support the distinction of categorical versus coordinate spatial processing, and suggest that these two basic relational processes are selectively affected by female sex hormones and differentially effective in transforming and handling temporal patterns as spatial relations in the context of multitasking.

Concurrent negotiation and coordination for grid resource coallocation.

PubMed

Sim, Kwang Mong; Shi, Benyun

2010-06-01

Bolstering resource coallocation is essential for realizing the Grid vision, because computationally intensive applications often require multiple computing resources from different administrative domains. Given that resource providers and consumers may have different requirements, successfully obtaining commitments through concurrent negotiations with multiple resource providers to simultaneously access several resources is a very challenging task for consumers. The impetus of this paper is that it is one of the earliest works that consider a concurrent negotiation mechanism for Grid resource coallocation. The concurrent negotiation mechanism is designed for 1) managing (de)commitment of contracts through one-to-many negotiations and 2) coordination of multiple concurrent one-to-many negotiations between a consumer and multiple resource providers. The novel contributions of this paper are devising 1) a utility-oriented coordination (UOC) strategy, 2) three classes of commitment management strategies (CMSs) for concurrent negotiation, and 3) the negotiation protocols of consumers and providers. Implementing these ideas in a testbed, three series of experiments were carried out in a variety of settings to compare the following: 1) the CMSs in this paper with the work of others in a single one-to-many negotiation environment for one resource where decommitment is allowed for both provider and consumer agents; 2) the performance of the three classes of CMSs in different resource market types; and 3) the UOC strategy with the work of others [e.g., the patient coordination strategy (PCS )] for coordinating multiple concurrent negotiations. Empirical results show the following: 1) the UOC strategy achieved higher utility, faster negotiation speed, and higher success rates than PCS for different resource market types; and 2) the CMS in this paper achieved higher final utility than the CMS in other works. Additionally, the properties of the three classes of CMSs in different kinds of resource markets are also verified.

Brain-Derived Neurotrophic Factor (BDNF) and Traumatic Brain Injury (Head and Spinal)

DTIC Science & Technology

2000-01-01

phosphatidylinositol 3-kinase are involved in brain-derived neurotrophic factor- mediated survival and neuritogenesis of the neuroblastoma cell line ... SH - SY5Y , J. Neurochem. 73 (1999) 1409-1421. 15. Gottshalk, W.A., Jiang, H., Tartaglia, N., Feng, L., Figurov, A., Lu, B., Signaling mechanisms...NT-6), and neurotrophin-7 (NT-7) (4, 5, 24, 80). Neurotrophins are believed to promote their cell survival, growth, and differentiation effects

Quantitative Tractography and Volumetric MRI in Blast and Blunt Force TBI: Predictors of Neurocognitive and Behavioral Outcome

DTIC Science & Technology

2016-10-01

are related to mechanism of injury as well as white matter integrity using diffusion tensor imaging (DTI). We are also collecting and analyzing...APOE ε4] and brain-derived neurotrophic factor [BDNF]) to brain integrity , neuropsychological functioning, and neurobehavioral outcome. 15. SUBJECT...contribution of genetic factors (Apolipoprotein-E ε-4 [APOE ε4] and brain-derived neurotrophic factor [BDNF]) to brain integrity , neuropsychological

LIF is more potent than BDNF in promoting neurite outgrowth of mammalian auditory neurons in vitro.

PubMed

Gillespie, L N; Clark, G M; Bartlett, P F; Marzella, P L

2001-02-12

Neurotrophic factors are known to play a crucial role in the elongation and guidance of auditory nerve fibres to their targets within the organ of Corti. Maintenance of these neural connections following deafness would clearly influence the efficacy of therapies for hearing recovery. The growth factors leukaemia inhibitory factor (LIF), brain-derived neurotrophic factor (BDNF) and transforming growth factor-beta 5 (TGF-beta5) were tested for their efficacy in promoting neurite outgrowth from dissociated cultures of early postnatal rat auditory neurons. Our results indicate that while BDNF enhances neurite outgrowth in a strong fashion, LIF is more potent; moreover, the combined administration of both factors has even greater neuritogenic capacities. TGF-beta5, although neurotrophic, has no neuritogenic activity on cultured auditory neurons. LIF and BDNF may therefore be potential candidates when developing pharmacological therapies for hearing recovery.

Protective effects of nicergoline against neuronal cell death induced by activated microglia and astrocytes.

PubMed

Mizuno, Tetsuya; Kuno, Reiko; Nitta, Atsumi; Nabeshima, Toshitaka; Zhang, Guiqin; Kawanokuchi, Jun; Wang, Jinyan; Jin, Shijie; Takeuchi, Hideyuki; Suzumura, Akio

2005-12-20

We examined the neuroprotective role of nicergoline in neuron-microglia or neuron-astrocytes co-cultures. Nicergoline, an ergoline derivative, significantly suppressed the neuronal cell death induced by co-culture with activated microglia or astrocytes stimulated with lipopolysaccharide (LPS) and interferon (IFN)-gamma. To elucidate the mechanism by which nicergoline exerts a neuroprotective effect, we examined the production of inflammatory mediators and neurotrophic factors in activated microglia and astrocytes following nicergoline treatment. In microglia stimulated with LPS and IFN-gamma, nicergoline suppressed the production of superoxide anions, interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha in a dose-dependent manner. In astrocytes, nicergoline also suppressed the production of proinflammatory cytokines and enhanced brain-derived neurotrophic factor (BDNF). Thus, nicergoline-mediated neuroprotection resulted primarily from the inhibition of inflammatory mediators and the upregulation of neurotrophic factors by glial cells.

Improvisation and the self-organization of multiple musical bodies.

PubMed

Walton, Ashley E; Richardson, Michael J; Langland-Hassan, Peter; Chemero, Anthony

2015-01-01

Understanding everyday behavior relies heavily upon understanding our ability to improvise, how we are able to continuously anticipate and adapt in order to coordinate with our environment and others. Here we consider the ability of musicians to improvise, where they must spontaneously coordinate their actions with co-performers in order to produce novel musical expressions. Investigations of this behavior have traditionally focused on describing the organization of cognitive structures. The focus, here, however, is on the ability of the time-evolving patterns of inter-musician movement coordination as revealed by the mathematical tools of complex dynamical systems to provide a new understanding of what potentiates the novelty of spontaneous musical action. We demonstrate this approach through the application of cross wavelet spectral analysis, which isolates the strength and patterning of the behavioral coordination that occurs between improvising musicians across a range of nested time-scales. Revealing the sophistication of the previously unexplored dynamics of movement coordination between improvising musicians is an important step toward understanding how creative musical expressions emerge from the spontaneous coordination of multiple musical bodies.

Improvisation and the self-organization of multiple musical bodies

PubMed Central

Walton, Ashley E.; Richardson, Michael J.; Langland-Hassan, Peter; Chemero, Anthony

2015-01-01

Understanding everyday behavior relies heavily upon understanding our ability to improvise, how we are able to continuously anticipate and adapt in order to coordinate with our environment and others. Here we consider the ability of musicians to improvise, where they must spontaneously coordinate their actions with co-performers in order to produce novel musical expressions. Investigations of this behavior have traditionally focused on describing the organization of cognitive structures. The focus, here, however, is on the ability of the time-evolving patterns of inter-musician movement coordination as revealed by the mathematical tools of complex dynamical systems to provide a new understanding of what potentiates the novelty of spontaneous musical action. We demonstrate this approach through the application of cross wavelet spectral analysis, which isolates the strength and patterning of the behavioral coordination that occurs between improvising musicians across a range of nested time-scales. Revealing the sophistication of the previously unexplored dynamics of movement coordination between improvising musicians is an important step toward understanding how creative musical expressions emerge from the spontaneous coordination of multiple musical bodies. PMID:25941499

Pharmacological profile of brain-derived neurotrophic factor (BDNF) splice variant translation using a novel drug screening assay: a "quantitative code".

PubMed

Vaghi, Valentina; Polacchini, Alessio; Baj, Gabriele; Pinheiro, Vera L M; Vicario, Annalisa; Tongiorgi, Enrico

2014-10-03

The neurotrophin brain-derived neurotrophic factor (BDNF) is a key regulator of neuronal development and plasticity. BDNF is a major pharmaceutical target in neurodevelopmental and psychiatric disorders. However, pharmacological modulation of this neurotrophin is challenging because BDNF is generated by multiple, alternatively spliced transcripts with different 5'- and 3'UTRs. Each BDNF mRNA variant is transcribed independently, but translation regulation is unknown. To evaluate the translatability of BDNF transcripts, we developed an in vitro luciferase assay in human neuroblastoma cells. In unstimulated cells, each BDNF 5'- and 3'UTR determined a different basal translation level of the luciferase reporter gene. However, constructs with either a 5'UTR or a 3'UTR alone showed poor translation modulation by BDNF, KCl, dihydroxyphenylglycine, AMPA, NMDA, dopamine, acetylcholine, norepinephrine, or serotonin. Constructs consisting of the luciferase reporter gene flanked by the 5'UTR of one of the most abundant BDNF transcripts in the brain (exons 1, 2c, 4, and 6) and the long 3'UTR responded selectively to stimulation with the different receptor agonists, and only transcripts 2c and 6 were increased by the antidepressants desipramine and mirtazapine. We propose that BDNF mRNA variants represent "a quantitative code" for regulated expression of the protein. Thus, to discriminate the efficacy of drugs in stimulating BDNF synthesis, it is appropriate to use variant-specific in vitro screening tests. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

A meta-analytic review of the effects of exercise on brain-derived neurotrophic factor.

PubMed

Szuhany, Kristin L; Bugatti, Matteo; Otto, Michael W

2015-01-01

Consistent evidence indicates that exercise improves cognition and mood, with preliminary evidence suggesting that brain-derived neurotrophic factor (BDNF) may mediate these effects. The aim of the current meta-analysis was to provide an estimate of the strength of the association between exercise and increased BDNF levels in humans across multiple exercise paradigms. We conducted a meta-analysis of 29 studies (N = 1111 participants) examining the effect of exercise on BDNF levels in three exercise paradigms: (1) a single session of exercise, (2) a session of exercise following a program of regular exercise, and (3) resting BDNF levels following a program of regular exercise. Moderators of this effect were also examined. Results demonstrated a moderate effect size for increases in BDNF following a single session of exercise (Hedges' g = 0.46, p < 0.001). Further, regular exercise intensified the effect of a session of exercise on BDNF levels (Hedges' g = 0.59, p = 0.02). Finally, results indicated a small effect of regular exercise on resting BDNF levels (Hedges' g = 0.27, p = 0.005). When analyzing results across paradigms, sex significantly moderated the effect of exercise on BDNF levels, such that studies with more women showed less BDNF change resulting from exercise. Effect size analysis supports the role of exercise as a strategy for enhancing BDNF activity in humans, but indicates that the magnitude of these effects may be lower in females relative to males. Copyright © 2014 Elsevier Ltd. All rights reserved.

A meta-analytic review of the effects of exercise on brain-derived neurotrophic factor

PubMed Central

Szuhany, Kristin L.; Bugatti, Matteo; Otto, Michael W.

2014-01-01

Consistent evidence indicates that exercise improves cognition and mood, with preliminary evidence suggesting that brain-derived neurotrophic factor (BDNF) may mediate these effects. The aim of the current meta-analysis was to provide an estimate of the strength of the association between exercise and increased BDNF levels in humans across multiple exercise paradigms. We conducted a meta-analysis of 29 studies (N = 1,111 participants) examining the effect of exercise on BDNF levels in three exercise paradigms: (1) a single session of exercise, (2) a session of exercise following a program of regular exercise, and (3) resting BDNF levels following a program of regular exercise. Moderators of this effect were also examined. Results demonstrated a moderate effect size for increases in BDNF following a single session of exercise (Hedges’ g = 0.46, p < 0.001). Further, regular exercise intensified the effect of a session of exercise on BDNF levels (Hedges’ g = 0.58, p = 0.02). Finally, results indicated a small effect of regular exercise on resting BDNF levels (Hedges’ g = 0.28, p = 0.005). When analyzing results across paradigms, sex significantly moderated the effect of exercise on BDNF levels, such that studies with more women showed less BDNF change resulting from exercise. Effect size analysis supports the role of exercise as a strategy for enhancing BDNF activity in humans, but indicates that the magnitude of these effects may be lower in females relative to males. PMID:25455510

Brain derived neurotrophic factor gene (BDNF) and personality traits: the modifying effect of season of birth and sex.

PubMed

Kazantseva, A; Gaysina, D; Kutlumbetova, Yu; Kanzafarova, R; Malykh, S; Lobaskova, M; Khusnutdinova, E

2015-01-02

Personality traits are complex phenotypes influenced by interactions of multiple genetic variants of small effect and environmental factors. It has been suggested that the brain derived neurotrophic factor gene (BDNF) is involved in personality traits. Season of birth (SOB) has also been shown to affect personality traits due to its influences on brain development during prenatal and early postnatal periods. The present study aimed to investigate the effects of BDNF on personality traits; and the modifying effects of SOB and sex on associations between BDNF and personality traits. A sample of 1018 young adults (68% women; age range 17-25years) of Caucasian origin from the Russian Federation was assessed on personality traits (Novelty Seeking, Harm Avoidance, Reward Dependence, Persistence, Self-directedness, Cooperativeness, Self-transcendence) with the Temperament and Character Inventory-125 (TCI-125). Associations between personality traits and 12 BDNF SNPs were tested using linear regression models. The present study demonstrated the effect of rs11030102 on Persistence in females only (PFDR=0.043; r(2)=1.3%). There were significant interaction effects between Val66Met (rs6265) and SOB (PFDR=0.048, r(2)=1.4%), and between rs2030323 and SOB (PFDR=0.042, r(2)=1.3%), on Harm Avoidance. Our findings provide evidence for the modifying effect of SOB on the association between BDNF and Harm Avoidance, and for the modifying effect of sex on the association between BDNF and Persistence. Copyright © 2014 Elsevier Inc. All rights reserved.

Protective Effects Induced by Microwave-Assisted Aqueous Harpagophytum Extract on Rat Cortex Synaptosomes Challenged with Amyloid β-Peptide.

PubMed

Ferrante, Claudio; Recinella, Lucia; Locatelli, Marcello; Guglielmi, Paolo; Secci, Daniela; Leporini, Lidia; Chiavaroli, Annalisa; Leone, Sheila; Martinotti, Sara; Brunetti, Luigi; Vacca, Michele; Menghini, Luigi; Orlando, Giustino

2017-08-01

Harpagophytum procumbens is a plant species that displays anti-inflammatory properties in multiple tissues. The iridoid glycosides arpagoside, harpagide, and procumbide appear to be the most therapeutically important constituents. In addition, harpagoside treatment exerted neuroprotective effects both in vitro and in vivo. Considering these findings, the aim of the present work is to explore the possible protective role of the previously described microwave-assisted aqueous extract of H. procumbens on rat hypothalamic (Hypo-E22) cells, and in rat cortex challenged with amyloid β-peptide (1-40). In this context, we assayed the protective effects induced by H. procumbens by measuring the levels of malondialdehyde, 3-hydroxykynurenine (3-HK), brain-derived neurotrophic factor, and tumor necrosis factor-α, 3-HK. Finally, we evaluated the effects of H. procumbens treatment on cortex levels of dopamine, norepinephrine, and serotonin. H. procumbens extract was well tolerated by Hypo-E22 cells and upregulated brain-derived neurotrophic factor gene expression but down-regulated tumor necrosis factor-α gene expression. In addition, the extract reduced amyloid β-peptide stimulation of malondialdehyde and 3-HK and blunted the decrease of dopamine, norepinephrine, and serotonin, in the cortex. In this context, our work supports further studies for the evaluation and confirmation of Harpagophytum in the management of the clinical symptoms related to Alzheimer's disease. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Neuroprotective effects of placenta-derived mesenchymal stromal cells in a rat model of experimental autoimmune encephalomyelitis.

PubMed

Selim, Assmaa O; Selim, Sally A; Shalaby, Sally M; Mosaad, Hala; Saber, Taisir

2016-09-01

Current therapies for multiple sclerosis (MS) are largely palliative, not curative. Mesenchymal stromal cells (MSCs) harbor regenerative and immunosuppressive functions, indicating a potential therapy for MS. A preparation of MSCs derived from full-term human placenta (PDMSCs) is a new approach in the treatment of patients with MS. This study aimed to rule out the possible therapy by PDMSCs in experimental autoimmune encephalomyelitis (EAE), a rat model of MS. Thirty-five female Wistar rats were classified into the following groups: I, control; II, EAE untreated; III and IV, EAE treated with phosphate-buffered saline (PBS) at 9 and 16 days post-immunization (dpi), respectively; V and VI, EAE treated with PDMSCs at 9 and 16 dpi, respectively. Intravenous administration of PDMSCs at 9 or 16 dpi significantly ameliorated the disease course, decreasing brain inflammation and degenerating neurons. A reduction of axonal damage as well as an increase of oligodendrocyte precursors were recorded. Moreover, there was an engraftment of the PDMSCs into the brain tissue. Human brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and neurotrophin 3 (NTF3) were significantly expressed in brains of rats treated by PDMSCs. Human PDMSCs have demonstrated striking therapeutic effects when delivered at the onset or at the peak of the disease. PDMSCs have direct neurotrophic support after their engraftment within the lesion through expression of the neurotrophins. Copyright © 2016 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Effect of childhood maltreatment and brain-derived neurotrophic factor on brain morphology

PubMed Central

Schmaal, Lianne; Jansen, Rick; Milaneschi, Yuri; Opmeer, Esther M.; Elzinga, Bernet M.; van der Wee, Nic J. A.; Veltman, Dick J.; Penninx, Brenda W. J. H.

2016-01-01

Childhood maltreatment (CM) has been associated with altered brain morphology, which may partly be due to a direct impact on neural growth, e.g. through the brain-derived neurotrophic factor (BDNF) pathway. Findings on CM, BDNF and brain volume are inconsistent and have never accounted for the entire BDNF pathway. We examined the effects of CM, BDNF (genotype, gene expression and protein level) and their interactions on hippocampus, amygdala and anterior cingulate cortex (ACC) morphology. Data were collected from patients with depression and/or an anxiety disorder and healthy subjects within the Netherlands Study of Depression and Anxiety (NESDA) (N = 289). CM was assessed using the Childhood Trauma Interview. BDNF Val66Met genotype, gene expression and serum protein levels were determined in blood and T1 MRI scans were acquired at 3T. Regional brain morphology was assessed using FreeSurfer. Covariate-adjusted linear regression analyses were performed. Amygdala volume was lower in maltreated individuals. This was more pronounced in maltreated met-allele carriers. The expected positive relationship between BDNF gene expression and volume of the amygdala is attenuated in maltreated subjects. Finally, decreased cortical thickness of the ACC was identified in maltreated subjects with the val/val genotype. CM was associated with altered brain morphology, partly in interaction with multiple levels of the BNDF pathway. Our results suggest that CM has different effects on brain morphology in met-carriers and val-homozygotes and that CM may disrupt the neuroprotective effect of BDNF. PMID:27405617

Early cognitive impairment along with decreased stress-induced BDNF in male and female patients with newly diagnosed multiple sclerosis.

PubMed

Prokopova, Barbora; Hlavacova, Natasa; Vlcek, Miroslav; Penesova, Adela; Grunnerova, Lucia; Garafova, Alexandra; Turcani, Peter; Kollar, Branislav; Jezova, Daniela

2017-01-15

The aim of this study was to evaluate neuroendocrine activation during stress in patients with recently diagnosed multiple sclerosis before starting the immunomodulatory therapy (EDSS score≤2.0). We verified the hypothesis that certain cognitive and affective dysfunction is present already at this early stage of the disease. The sample consisted of 38 subjects, which involved patients who were recently diagnosed multiple sclerosis and age- and sex-matched healthy volunteers. Stroop test served as mental stress model enabling measurement of cognitive performance. Present results showed increased state anxiety, depression scores and poorer performance in the Stroop test in the group of patients compared to healthy subjects. The cognitive dysfunction was particularly evident in male patients with simultaneously decreased concentrations of the brain-derived neurotrophic factor (BDNF) in plasma. The patients at this stage of the disease have not yet developed the hyperactivity of the hypothalamic-pituitary-adrenocortical axis. They showed normal levels of plasma copeptin and reduced aldosterone response to mental stress test in women only. Concentrations of plasma copeptin were higher in men compared to women. Very early stages of multiple sclerosis are accompanied by disturbances in psychological well-being, mild cognitive dysfunction and decreased plasma concentrations of BDNF, particularly in male patients. Copyright © 2016. Published by Elsevier B.V.

Bridging animal and human models of exercise-induced brain plasticity

PubMed Central

Voss, Michelle W.; Vivar, Carmen; Kramer, Arthur F.; van Praag, Henriette

2015-01-01

Significant progress has been made in understanding the neurobiological mechanisms through which exercise protects and restores the brain. In this feature review, we integrate animal and human research, examining physical activity effects across multiple levels of description (neurons up to inter-regional pathways). We evaluate the influence of exercise on hippocampal structure and function, addressing common themes such as spatial memory and pattern separation, brain structure and plasticity, neurotrophic factors, and vasculature. Areas of research focused more within species, such as hippocampal neurogenesis in rodents, also provide crucial insight into the protective role of physical activity. Overall, converging evidence suggests exercise benefits brain function and cognition across the mammalian lifespan, which may translate into reduced risk for Alzheimer’s disease (AD) in humans. PMID:24029446

Gaze Stabilization During Locomotion Requires Full Body Coordination

NASA Technical Reports Server (NTRS)

Mulavara, A. P.; Miller, C. A.; Houser, J.; Richards, J. T.; Bloomberg, J. J.

2001-01-01

Maintaining gaze stabilization during locomotion places substantial demands on multiple sensorimotor subsystems for precise coordination. Gaze stabilization during locomotion requires eye-head-trunk coordination (Bloomberg, et al., 1997) as well as the regulation of energy flow or shock-wave transmission through the body at high impact phases with the support surface (McDonald, et al., 1997). Allowing these excessive transmissions of energy to reach the head may compromise gaze stability. Impairments in these mechanisms may lead to the oscillopsia and decreased dynamic visual acuity seen in crewmembers returning from short and long duration spaceflight, as well as in patients with vestibular disorders (Hillman, et al., 1999). Thus, we hypothesize that stabilized gaze during locomotion results from full-body coordination of the eye-head-trunk system combined with the lower limb apparatus. The goal of this study was to determine how multiple, interdependent full- body sensorimotor subsystems aiding gaze stabilization during locomotion are functionally coordinated, and how they adaptively respond to spaceffight.

Identifying and Coordinating Care for Complex Patients

PubMed Central

Rudin, Robert S.; Gidengil, Courtney A.; Predmore, Zachary; Schneider, Eric C.; Sorace, James; Hornstein, Rachel

2017-01-01

Abstract In the United States, a relatively small proportion of complex patients---defined as having multiple comorbidities, high risk for poor outcomes, and high cost---incur most of the nation's health care costs. Improved care coordination and management of complex patients could reduce costs while increasing quality of care. However, care coordination efforts face multiple challenges, such as segmenting populations of complex patients to better match their needs with the design of specific interventions, understanding how to reduce spending, and integrating care coordination programs into providers' care delivery processes. Innovative uses of analytics and health information technology (HIT) may address these challenges. Rudin and colleagues at RAND completed a literature review and held discussions with subject matter experts, reaching the conclusion that analytics and HIT are being used in innovative ways to coordinate care for complex patients but that the capabilities are limited, evidence of their effectiveness is lacking, and challenges are substantial, and important foundational work is still needed. PMID:28845354

The Neurotrophic Substances and Behavioral Recovery from Brain Damage.

DTIC Science & Technology

1984-11-01

neurotrophic substances that facilitate synthesis may be partially responsible for the com- neuronal regeneration" 12 pensatory effects of the NGF in...1962. Facilitation of simultaneous discrimination learning with strychnine sulphate. Psychopharmacologia 3: 166-172. 21. MEANS, E. D., AND D. K...34 ’- ,P ’% --- SALINE EFFECT 1071 28. SIESJO, B. K. 1981. Cell damage in the brain. A speculative synthesis . J. Cereb. Blood’ Flow Meiab. t: s155-slS5. 29

Corallocins A-C, Nerve Growth and Brain-Derived Neurotrophic Factor Inducing Metabolites from the Mushroom Hericium coralloides.

PubMed

Wittstein, Kathrin; Rascher, Monique; Rupcic, Zeljka; Löwen, Eduard; Winter, Barbara; Köster, Reinhard W; Stadler, Marc

2016-09-23

Three new natural products, corallocins A-C (1-3), along with two known compounds were isolated from the mushroom Hericium coralloides. Their benzofuranone and isoindolinone structures were elucidated by spectral methods. All corallocins induced nerve growth factor and/or brain-derived neurotrophic factor expression in human 1321N1 astrocytes. Furthermore, corallocin B showed antiproliferative activity against HUVEC and human cancer cell lines MCF-7 and KB-3-1.

In vivo screening reveals interactions between Drosophila Manf and genes involved in the mitochondria and the ubiquinone synthesis pathway.

PubMed

Lindström, Riitta; Lindholm, Päivi; Palgi, Mari; Saarma, Mart; Heino, Tapio I

2017-06-02

Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) and Cerebral Dopamine Neurotrophic Factor (CDNF) form an evolutionarily conserved family of neurotrophic factors. Orthologues for MANF/CDNF are the only neurotrophic factors as yet identified in invertebrates with conserved amino acid sequence. Previous studies indicate that mammalian MANF and CDNF support and protect brain dopaminergic system in non-cell-autonomous manner. However, MANF has also been shown to function intracellularly in the endoplasmic reticulum. To date, the knowledge on the interacting partners of MANF/CDNF and signaling pathways they activate is rudimentary. Here, we have employed the Drosophila genetics to screen for potential interaction partners of Drosophila Manf (DmManf) in vivo. We first show that DmManf plays a role in the development of Drosophila wing. We exploited this function by using Drosophila UAS-RNAi lines and discovered novel genetic interactions of DmManf with genes known to function in the mitochondria. We also found evidence of an interaction between DmManf and the Drosophila homologue encoding Ku70, the closest structural homologue of SAP domain of mammalian MANF. In addition to the previously known functions of MANF/CDNF protein family, DmManf also interacts with mitochondria-related genes. Our data supports the functional importance of these evolutionarily significant proteins and provides new insights for the future studies.

Protective effects of low-intensity pulsed ultrasound on aluminum-induced cerebral damage in Alzheimer's disease rat model

NASA Astrophysics Data System (ADS)

Lin, Wei-Ting; Chen, Ran-Chou; Lu, Wen-Wei; Liu, Shing-Hwa; Yang, Feng-Yi

2015-04-01

The protein expressions of neurotrophic factors can be enhanced by low-intensity pulsed ultrasound (LIPUS) stimulation in the brain. The purpose of this study was to demonstrate the protective effect of LIPUS stimulation against aluminum-induced cerebral damage in Alzheimer's disease rat model. LIPUS was administered 7 days before each aluminum chloride (AlCl3) administration, and concomitantly given with AlCl3 daily for a period of 6 weeks. Neurotrophic factors in hippocampus were measured by western blot analysis. Behavioral changes in the Morris water maze and elevated plus maze were examined in rats after administration of AlCl3. Various biochemical analyses were performed to evaluate the extent of brain damages. LIPUS is capable of prompting levels of brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and vascular endothelial growth factor (VEGF) in rat brain. AlCl3 administration resulted in a significant increase in the aluminum concentration, acetylcholinesterase activity and beta-amyloid (Aβ) deposition in AlCl3 treated rats. LIPUS stimulation significantly attenuated aluminum concentration, acetylcholinesterase activity, Aβ deposition and karyopyknosis in AlCl3 treated rats. Furthermore, LIPUS significantly improved memory retention in AlCl3-induced memory impairment. These experimental results indicate that LIPUS has neuroprotective effects against AlCl3-induced cerebral damages and cognitive dysfunction.

Current disease modifying approaches to treat Parkinson's disease.

PubMed

Lindholm, Dan; Mäkelä, Johanna; Di Liberto, Valentina; Mudò, Giuseppa; Belluardo, Natale; Eriksson, Ove; Saarma, Mart

2016-04-01

Parkinson's disease (PD is a progressive neurological disorder characterized by the degeneration and death of midbrain dopamine and non-dopamine neurons in the brain leading to motor dysfunctions and other symptoms, which seriously influence the quality of life of PD patients. The drug L-dopa can alleviate the motor symptoms in PD, but so far there are no rational therapies targeting the underlying neurodegenerative processes. Despite intensive research, the molecular mechanisms causing neuronal loss are not fully understood which has hampered the development of new drugs and disease-modifying therapies. Neurotrophic factors are by virtue of their survival promoting activities attract candidates to counteract and possibly halt cell degeneration in PD. In particular, studies employing glial cell line-derived neurotrophic factor (GDNF) and its family member neurturin (NRTN), as well as the recently described cerebral dopamine neurotrophic factor (CDNF) and the mesencephalic astrocyte-derived neurotrophic factor (MANF) have shown positive results in protecting and repairing dopaminergic neurons in various models of PD. Other substances with trophic actions in dopaminergic neurons include neuropeptides and small compounds that target different pathways impaired in PD, such as increased cell stress, protein handling defects, dysfunctional mitochondria and neuroinflammation. In this review, we will highlight the recent developments in this field with a focus on trophic factors and substances having the potential to beneficially influence the viability and functions of dopaminergic neurons as shown in preclinical or in animal models of PD.

Neurotrophin expression and laryngeal muscle pathophysiology following recurrent laryngeal nerve transection

PubMed Central

WANG, BAOXIN; YUAN, JUNJIE; XU, JIAFENG; XIE, JIN; WANG, GUOLIANG; DONG, PIN

2016-01-01

Laryngeal palsy often occurs as a result of recurrent laryngeal or vagal nerve injury during oncological surgery of the head and neck, affecting quality of life and increasing economic burden. Reinnervation following recurrent laryngeal nerve (RLN) injury is difficult despite development of techniques, such as neural anastomosis, nerve grafting and creation of a laryngeal muscle pedicle. In the present study, due to the limited availability of human nerve tissue for research, a rat model was used to investigate neurotrophin expression and laryngeal muscle pathophysiology in RLN injury. Twenty-five male Sprague-Dawley rats underwent right RLN transection with the excision of a 5-mm segment. Vocal fold movements, vocalization, histology and immunostaining were evaluated at different time-points (3, 6, 10 and 16 weeks). Although vocalization was restored, movement of the vocal fold failed to return to normal levels following RLN injury. The expression of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor differed in the thyroarytenoid (TA) and posterior cricoarytenoid muscles. The number of axons did not increase to baseline levels over time. Furthermore, normal muscle function was unlikely with spontaneous reinnervation. During regeneration following RLN injury, differences in the expression levels of neurotrophic factors may have resulted in preferential reinnervation of the TA muscles. Data from the present study indicated that neurotrophic factors may be applied for restoring the function of the laryngeal nerve following recurrent injury. PMID:26677138

Neurotrophin expression and laryngeal muscle pathophysiology following recurrent laryngeal nerve transection.

PubMed

Wang, Baoxin; Yuan, Junjie; Xu, Jiafeng; Xie, Jin; Wang, Guoliang; Dong, Pin

2016-02-01

Laryngeal palsy often occurs as a result of recurrent laryngeal or vagal nerve injury during oncological surgery of the head and neck, affecting quality of life and increasing economic burden. Reinnervation following recurrent laryngeal nerve (RLN) injury is difficult despite development of techniques, such as neural anastomosis, nerve grafting and creation of a laryngeal muscle pedicle. In the present study, due to the limited availability of human nerve tissue for research, a rat model was used to investigate neurotrophin expression and laryngeal muscle pathophysiology in RLN injury. Twenty-five male Sprague-Dawley rats underwent right RLN transection with the excision of a 5-mm segment. Vocal fold movements, vocalization, histology and immunostaining were evaluated at different time-points (3, 6, 10 and 16 weeks). Although vocalization was restored, movement of the vocal fold failed to return to normal levels following RLN injury. The expression of brain‑derived neurotrophic factor and glial cell line-derived neurotrophic factor differed in the thyroarytenoid (TA) and posterior cricoarytenoid muscles. The number of axons did not increase to baseline levels over time. Furthermore, normal muscle function was unlikely with spontaneous reinnervation. During regeneration following RLN injury, differences in the expression levels of neurotrophic factors may have resulted in preferential reinnervation of the TA muscles. Data from the present study indicated that neurotrophic factors may be applied for restoring the function of the laryngeal nerve following recurrent injury.

Performance on the Wisconsin card-sorting test and serum levels of glial cell line-derived neurotrophic factor in patients with major depressive disorder.

PubMed

Zhang, Xiaobin; Ru, Bu; Sha, Weiwei; Xin, Wang; Zhou, Honghui; Zhang, Yumei

2014-09-01

Some evidence suggests that neurotrophic growth factor systems might be involved in the etiology of major depressive disorder (MDD). Glial cell line-derived neurotrophic factor (GDNF) is a neurotrophic factor from the transforming growth factor-β family that plays a role in the development and function of the brain. This study aimed to test whether GDNF in serum was abnormal in MDD, and whether it was related to the cognitive impairment of MDD. Serum GDNF levels in MDD patients (n = 32) and normal controls (n = 32) were measured with the enzyme-linked immunosorbent assay method. All subjects were assessed for performance on the Wisconsin card-sorting test (WCST). Performance on the WCST in MDD patients was significantly poorer than that in controls. Serum GDNF levels in MDD patients were significantly decreased compared to that of the control subjects (P < 0.001). Furthermore, the decrease in the serum GDNF levels positively correlated with performance in the WCST-% CONC and negatively with performance in the WCST-P in MDD patients. The findings suggest that MDD patients have extensive impairments of executive functioning, and lower serum GDNF might be involved in the pathogenesis of MDD, which may be associated with the cognitive dysfunction in MDD patients. © 2014 Wiley Publishing Asia Pty Ltd.

Neuroprotective therapies in glaucoma: II. Genetic nanotechnology tools.

PubMed

Nafissi, Nafiseh; Foldvari, Marianna

2015-01-01

Neurotrophic factor genome engineering could have many potential applications not only in the deeper understanding of neurodegenerative disorders but also in improved therapeutics. The fields of nanomedicine, regenerative medicine, and gene/cell-based therapy have been revolutionized by the development of safer and efficient non-viral technologies for gene delivery and genome editing with modern techniques for insertion of the neurotrophic factors into clinically relevant cells for a more sustained pharmaceutical effect. It has been suggested that the long-term expression of neurotrophic factors is the ultimate approach to prevent and/or treat neurodegenerative disorders such as glaucoma in patients who do not respond to available treatments or are at the progressive stage of the disease. Recent preclinical research suggests that novel neuroprotective gene and cell therapeutics could be promising approaches for both non-invasive neuroprotection and regenerative functions in the eye. Several progenitor and retinal cell types have been investigated as potential candidates for glaucoma neurotrophin therapy either as targets for gene therapy, options for cell replacement therapy, or as vehicles for gene delivery. Therefore, in parallel with deeper understanding of the specific protective effects of different neurotrophic factors and the potential therapeutic cell candidates for glaucoma neuroprotection, the development of non-invasive and highly specific gene delivery methods with safe and effective technologies to modify cell candidates for life-long neuroprotection in the eye is essential before investing in this field.

Early neurotrophic pharmacotherapy rescues developmental delay and Alzheimer’s-like memory deficits in the Ts65Dn mouse model of Down syndrome

PubMed Central

Kazim, Syed Faraz; Blanchard, Julie; Bianchi, Riccardo; Iqbal, Khalid

2017-01-01

Down syndrome (DS), caused by trisomy 21, is the most common genetic cause of intellectual disability and is associated with a greatly increased risk of early-onset Alzheimer’s disease (AD). The Ts65Dn mouse model of DS exhibits several key features of the disease including developmental delay and AD-like cognitive impairment. Accumulating evidence suggests that impairments in early brain development caused by trisomy 21 contribute significantly to memory deficits in adult life in DS. Prenatal genetic testing to diagnose DS in utero, provides the novel opportunity to initiate early pharmacological treatment to target this critical period of brain development. Here, we report that prenatal to early postnatal treatment with a ciliary neurotrophic factor (CNTF) small-molecule peptide mimetic, Peptide 021 (P021), rescued developmental delay in pups and AD-like hippocampus-dependent memory impairments in adult life in Ts65Dn mice. Furthermore, this treatment prevented pre-synaptic protein deficit, decreased glycogen synthase kinase-3beta (GSK3β) activity, and increased levels of synaptic plasticity markers including brain derived neurotrophic factor (BNDF) and phosphorylated CREB, both in young (3-week-old) and adult (~ 7-month-old) Ts65Dn mice. These findings provide novel evidence that providing neurotrophic support during early brain development can prevent developmental delay and AD-like memory impairments in a DS mouse model. PMID:28368015

Treatment of neurotrophic keratopathy with nicergoline.

PubMed

Lee, Young-Chun; Kim, Su-Young

2015-03-01

The aim of this study was to determine the effect of nicergoline in patients with neurotrophic keratopathy. This is a prospective, noncomparative interventional study. The study included 27 eyes of 24 patients with neurotrophic keratopathy who were unresponsive to conventional therapy. Patients were treated with 10 mg of oral nicergoline twice daily for at least 2 weeks. Slit-lamp examination, photography, corneal fluorescein dye testing, Cochet-Bonnet corneal sensitivity, and best-corrected visual acuity tests were performed before and after treatment. Tear nerve growth factor levels were measured before and after treatment. In 23 eyes (85%), epithelial defects healed completely between 7 and 30 days of treatment with nicergoline (mean, 15.6 ± 8.0 days). Epithelial defects persisted in 4 eyes (15%). The mean corneal sensitivity before and after treatment with nicergoline was 20.5 ± 8.5 and 30.2 ± 10.8 mm, respectively (P < 0.001). The best-corrected visual acuity (measured in units according to the logarithm of the minimum angle of resolution) was significantly improved from 1.1 ± 0.6 to 0.8 ± 0.6 (P < 0.001). The tear nerve growth factor levels were significantly higher ranging from 3.2 ± 0.3 to 6.2 ± 0.3 pg/mL (P < 0.001). Treatment with nicergoline helps patients with neurotrophic keratopathy in whom conventional treatment has failed.

An Expanded Theoretical Framework of Care Coordination Across Transitions in Care Settings.

PubMed

Radwin, Laurel E; Castonguay, Denise; Keenan, Carolyn B; Hermann, Cherice

2016-01-01

For many patients, high-quality, patient-centered, and cost-effective health care requires coordination among multiple clinicians and settings. Ensuring optimal care coordination requires a clear understanding of how clinician activities and continuity during transitions affect patient-centeredness and quality outcomes. This article describes an expanded theoretical framework to better understand care coordination. The framework provides clear articulation of concepts. Examples are provided of ways to measure the concepts.

Better dual-task processing in simultaneous interpreters

PubMed Central

Strobach, Tilo; Becker, Maxi; Schubert, Torsten; Kühn, Simone

2015-01-01

Simultaneous interpreting (SI) is a highly complex activity and requires the performance and coordination of multiple, simultaneous tasks: analysis and understanding of the discourse in a first language, reformulating linguistic material, storing of intermediate processing steps, and language production in a second language among others. It is, however, an open issue whether persons with experience in SI possess superior skills in coordination of multiple tasks and whether they are able to transfer these skills to lab-based dual-task situations. Within the present study, we set out to explore whether interpreting experience is associated with related higher-order executive functioning in the context of dual-task situations of the Psychological Refractory Period (PRP) type. In this PRP situation, we found faster reactions times in participants with experience in simultaneous interpretation in contrast to control participants without such experience. Thus, simultaneous interpreters possess superior skills in coordination of multiple tasks in lab-based dual-task situations. PMID:26528232

New nonlinear control algorithms for multiple robot arms

NASA Technical Reports Server (NTRS)

Tarn, T. J.; Bejczy, A. K.; Yun, X.

1988-01-01

Multiple coordinated robot arms are modeled by considering the arms as closed kinematic chains and as a force-constrained mechanical system working on the same object simultaneously. In both formulations, a novel dynamic control method is discussed. It is based on feedback linearization and simultaneous output decoupling technique. By applying a nonlinear feedback and a nonlinear coordinate transformation, the complicated model of the multiple robot arms in either formulation is converted into a linear and output decoupled system. The linear system control theory and optimal control theory are used to design robust controllers in the task space. The first formulation has the advantage of automatically handling the coordination and load distribution among the robot arms. In the second formulation, it was found that by choosing a general output equation it became possible simultaneously to superimpose the position and velocity error feedback with the force-torque error feedback in the task space.

Circadian control of p75 neurotrophin receptor leads to alternate activation of Nrf2 and c-Rel to reset energy metabolism in astrocytes via brain-derived neurotrophic factor.

PubMed

Ishii, Tetsuro; Warabi, Eiji; Mann, Giovanni E

2018-05-01

Circadian clock genes regulate energy metabolism partly through neurotrophins in the body. The low affinity neurotrophin receptor p75 NTR is a clock component directly regulated by the transcriptional factor Clock:Bmal1 complex. Brain-derived neurotrophic factor (BDNF) is expressed in the brain and plays a key role in coordinating metabolic interactions between neurons and astrocytes. BDNF transduces signals through TrkB and p75 NTR receptors. This review highlights a novel molecular mechanism by which BDNF via circadian control of p75 NTR leads to daily resetting of glucose and glycogen metabolism in brain astrocytes to accommodate their functional interaction with neurons. Astrocytes store glycogen as an energy reservoir to provide active neurons with the glycolytic metabolite lactate. Astrocytes predominantly express the truncated receptor TrkB.T1 which lacks an intracellular receptor tyrosine kinase domain. TrkB.T1 retains the capacity to regulate cell morphology through regulation of Rho GTPases. In contrast, p75 NTR mediates generation of the bioactive lipid ceramide upon stimulation with BDNF and inhibits PKA activation. As ceramide directly activates PKCζ, we discuss the importance of the TrkB.T1-p75 NTR -ceramide-PKCζ signaling axis in the stimulation of glycogen and lipid synthesis and activation of RhoA. Ceramide-PKCζ-casein kinase 2 signaling activates Nrf2 to support oxidative phosphorylation via upregulation of antioxidant enzymes. In the absence of p75 NTR , TrkB.T1 functionally interacts with adenosine A 2A R and dopamine D1R receptors to enhance cAMP-PKA signaling and activate Rac1 and NF-κB c-Rel, favoring glycogen hydrolysis, gluconeogenesis and aerobic glycolysis. Thus, diurnal changes in p75 NTR levels in astrocytes resets energy metabolism via BDNF to accommodate their metabolic interaction with neurons. Copyright © 2018 Elsevier Inc. All rights reserved.

Fisetin Acts on Multiple Pathways to Reduce the Impact of Age and Disease on CNS Function

PubMed Central

Maher, Pamela

2017-01-01

It is becoming increasingly clear that neurological diseases are multi-factorial involving disruptions in multiple cellular systems. Thus, while each disease has its own initiating mechanisms and pathologies, certain common pathways appear to be involved in most, if not all, neurological diseases described to date. Thus, it is unlikely that modulating only a single factor will be effective at either preventing disease development or slowing disease progression. A better approach is to identify small (< 900 daltons) molecules that have multiple biological activities relevant to the maintenance of brain function. Over the last few years, we have identified an orally active, novel neuroprotective and cognition-enhancing molecule, the flavonoid fisetin. Fisetin not only has direct antioxidant activity but it can also increase the intracellular levels of glutathione, the major intracellular antioxidant. Fisetin can also activate key neurotrophic factor signaling pathways. In addition, it has anti-inflammatory activity against microglial cells and inhibits the activity of lipoxygenases, thereby reducing the production of pro-inflammatory eicosanoids and their by-products. This wide range of actions suggests that fisetin has the ability to reduce the impact of age-related neurological diseases on brain function. PMID:25961687

Progranulin genetic polymorphisms influence progression of disability and relapse recovery in multiple sclerosis.

PubMed

Vercellino, Marco; Fenoglio, Chiara; Galimberti, Daniela; Mattioda, Alessandra; Chiavazza, Carlotta; Binello, Eleonora; Pinessi, Lorenzo; Giobbe, Dario; Scarpini, Elio; Cavalla, Paola

2016-07-01

Progranulin (GRN) is a multifunctional protein involved in inflammation and repair, and also a neurotrophic factor critical for neuronal survival. Progranulin is strongly expressed in multiple sclerosis (MS) brains by macrophages and microglia. In this study we evaluated GRN genetic variability in 400 MS patients, in correlation with clinical variables such as disease severity and relapse recovery. We also evaluated serum progranulin levels in the different groups of GRN variants carriers. We found that incomplete recovery after a relapse is correlated with an increased frequency of the rs9897526 A allele (odds ratio (OR) 4.367, p = 0.005). A more severe disease course (Multiple Sclerosis Severity Score > 5) is correlated with an increased frequency of the rs9897526 A allele (OR 1.886, p = 0.002) and of the rs5848 T allele (OR 1.580, p = 0.019). Carriers of the variants associated with a more severe disease course (rs9897526 A, rs5848 T) have significantly lower levels of circulating progranulin (80.5 ± 9.1 ng/mL vs. 165.7 ng/mL, p = 0.01). GRN genetic polymorphisms likely influence disease course and relapse recovery in MS. © The Author(s), 2015.

Changes in Afferent Activity After Spinal Cord Injury

PubMed Central

de Groat, William C.; Yoshimura, Naoki

2010-01-01

Aims To summarize the changes that occur in the properties of bladder afferent neurons following spinal cord injury. Methods Literature review of anatomical, immunohistochemical, and pharmacologic studies of normal and dysfunctional bladder afferent pathways. Results Studies in animals indicate that the micturition reflex is mediated by a spinobulbospinal pathway passing through coordination centers (periaqueductal gray and pontine micturition center) located in the rostral brain stem. This reflex pathway, which is activated by small myelinated (Aδ) bladder afferent nerves, is in turn modulated by higher centers in the cerebral cortex involved in the voluntary control of micturition. Spinal cord injury at cervical or thoracic levels disrupts voluntary voiding, as well as the normal reflex pathways that coordinate bladder and sphincter function. Following spinal cord injury, the bladder is initially areflexic but then becomes hyperreflexic due to the emergence of a spinal micturition reflex pathway. The recovery of bladder function after spinal cord injury is dependent in part on the plasticity of bladder afferent pathways and the unmasking of reflexes triggered by unmyelinated, capsaicin-sensitive, C-fiber bladder afferent neurons. Plasticity is associated with morphologic, chemical, and electrical changes in bladder afferent neurons and appears to be mediated in part by neurotrophic factors released in the spinal cord and the peripheral target organs. Conclusions Spinal cord injury at sites remote from the lumbosacral spinal cord can indirectly influence properties of bladder afferent neurons by altering the function and chemical environment in the bladder or the spinal cord. PMID:20025033

Long-term delivery of brain-derived neurotrophic factor (BDNF) from nanoporous silica nanoparticles improves the survival of spiral ganglion neurons in vitro

PubMed Central

Warwas, Dawid P.; Ehlert, Nina; Lenarz, Thomas; Warnecke, Athanasia; Behrens, Peter

2018-01-01

Sensorineural hearing loss (SNHL) can be overcome by electrical stimulation of spiral ganglion neurons (SGNs) via a cochlear implant (CI). Restricted CI performance results from the spatial gap between the SGNs and the electrode, but the efficacy of CI is also limited by the degeneration of SGNs as one consequence of SHNL. In the healthy cochlea, the survival of SGNs is assured by endogenous neurotrophic support. Several applications of exogenous neurotrophic supply have been shown to reduce SGN degeneration in vitro and in vivo. In the present study, nanoporous silica nanoparticles (NPSNPs), with an approximate diameter of <100 nm, were loaded with the brain-derived neurotrophic factor (BDNF) to test their efficacy as long-term delivery system for neurotrophins. The neurotrophic factor was released constantly from the NPSNPs over a release period of 80 days when the surface of the nanoparticles had been modified with amino groups. Cell culture investigations with NIH3T3 fibroblasts attest a good general cytocompatibility of the NPSNPs. In vitro experiments with SGNs indicate a significantly higher survival rate of SGNs in cell cultures that contained BDNF-loaded nanoparticles compared to the control culture with unloaded NPSNPs (p<0.001). Importantly, also the amounts of BDNF released up to a time period of 39 days increased the survival rate of SGNs. Thus, NPSNPs carrying BDNF are suitable for the treatment of inner ear disease and for the protection and the support of SGNs. Their nanoscale nature and the fact that a direct contact of the nanoparticles and the SGNs is not necessary for neuroprotective effects, should allow for the facile preparation of nanocomposites, e.g., with biocompatible polymers, to install coatings on implants for the realization of implant-based growth factor delivery systems. PMID:29584754

In vitro assessment of TAT — Ciliary Neurotrophic Factor therapeutic potential for peripheral nerve regeneration

DOE Office of Scientific and Technical Information (OSTI.GOV)

Barbon, Silvia, E-mail: silvia.barbon@yahoo.it

In regenerative neurobiology, Ciliary Neurotrophic Factor (CNTF) is raising high interest as a multifunctional neurocytokine, playing a key role in the regeneration of injured peripheral nerves. Despite its promising trophic and regulatory activity, its clinical application is limited by the onset of severe side effects, due to the lack of efficient intracellular trafficking after administration. In this study, recombinant CNTF linked to the transactivator transduction domain (TAT) was investigated in vitro and found to be an optimized fusion protein which preserves neurotrophic activity, besides enhancing cellular uptake for therapeutic advantage. Moreover, a compelling protein delivery method was defined, in themore » future perspective of improving nerve regeneration strategies. Following determination of TAT-CNTF molecular weight and concentration, its specific effect on neural SH-SY5Y and PC12 cultures was assessed. Cell proliferation assay demonstrated that the fusion protein triggers PC12 cell growth within 6 h of stimulation. At the same time, the activation of signal transduction pathway and enhancement of cellular trafficking were found to be accomplished in both neural cell lines after specific treatment with TAT-CNTF. Finally, the recombinant growth factor was successfully loaded on oxidized polyvinyl alcohol (PVA) scaffolds, and more efficiently released when polymer oxidation rate increased. Taken together, our results highlight that the TAT domain addiction to the protein sequence preserves CNTF specific neurotrophic activity in vitro, besides improving cellular uptake. Moreover, oxidized PVA could represent an ideal biomaterial for the development of nerve conduits loaded with the fusion protein to be delivered to the site of nerve injury. - Highlights: • TAT-CNTF is an optimized fusion protein that preserves neurotrophic activity. • In neural cell lines, TAT-CNTF triggers the activation of signal transduction. • Fast cellular uptake of TAT-CNTF was accomplished after cell treatment. • TAT-CNTF can be efficiently loaded on oxidized PVA cylinders for local delivery. • TAT-CNTF features make it ideal for peripheral nerve regeneration therapies.« less

Regulatory Mechanisms Involved in the Expression of Brain-Derived Neurotrophic Factor and Glial Cell Line-Derived Neurotrophic Factor

DTIC Science & Technology

1996-03-01

neurotoxic dopamine analog that is taken up by nigral dopaminergic cells where it is metabolized to highly reactive oxygen free radicals that cause ...brain regions is elevated after other types of brain insults, including ischemia and hypoglycemia (see Lindvall et al. 1994 for review). Lindvall et a1...with kainic acid were also reported. These investigators also reported significant increases in BDNF mRNA levels in cultures of neonatal astrocytes

Neuropeptide cycloprolylglycine increases the levels of brain-derived neurotrophic factor in neuronal cells.

PubMed

Gudasheva, T A; Koliasnikova, K N; Antipova, T A; Seredenin, S B

2016-07-01

It was shown for the first time that the endogenous cyclic dipeptide cycloprolylglycine (CPG) at concentrations of 10(-7) and 10(-3) M and piracetam at a concentration of 10(-3) M increased the content of brainderived neurotrophic factor (BDNF) in the culture of neuronal cells in normal state and under conditions of glutamate and 6-oxydopamine neurotoxicity. This may indicate the possible involvement of BDNF in the mechanism of action of neuropeptide CPG and piracetam.

A novel method for improving the accuracy of coordinate transformation in multiple measurement systems

NASA Astrophysics Data System (ADS)

Liu, W. L.; Li, Y. W.

2017-09-01

Large-scale dimensional metrology usually requires a combination of multiple measurement systems, such as laser tracking, total station, laser scanning, coordinate measuring arm and video photogrammetry, etc. Often, the results from different measurement systems must be combined to provide useful results. The coordinate transformation is used to unify coordinate frames in combination; however, coordinate transformation uncertainties directly affect the accuracy of the final measurement results. In this paper, a novel method is proposed for improving the accuracy of coordinate transformation, combining the advantages of the best-fit least-square and radial basis function (RBF) neural networks. First of all, the configuration of coordinate transformation is introduced and a transformation matrix containing seven variables is obtained. Second, the 3D uncertainty of the transformation model and the residual error variable vector are established based on the best-fit least-square. Finally, in order to optimize the uncertainty of the developed seven-variable transformation model, we used the RBF neural network to identify the uncertainty of the dynamic, and unstructured, owing to its great ability to approximate any nonlinear function to the designed accuracy. Intensive experimental studies were conducted to check the validity of the theoretical results. The results show that the mean error of coordinate transformation decreased from 0.078 mm to 0.054 mm after using this method in contrast with the GUM method.

Generalization of rapidly recurring seizures is suppressed in mice lacking glial cell line-derived neurotrophic factor family receptor alpha2.

PubMed

Nanobashvili, A; Kokaia, Z; Lindvall, O

2003-01-01

Recent experimental evidence indicates that neurotrophic factors play a role in the pathophysiology of epilepsy. The objective of this study was to explore whether signaling through one of the glial cell line-derived neurotrophic factor family receptors, GFRalpha2, influences the severity of kindling-evoked, rapidly recurring seizures and the subsequent development of permanent hyperexcitability. We applied the rapid kindling model to adult mice, using 40 threshold stimulations delivered with 5-min interval in the ventral hippocampus. Generalized seizures were fewer and developed later in response to kindling stimulations in mice lacking GFRalpha2. However, GFRalpha2 gene deletion did not influence the acquisition of the permanent abnormal excitability as assessed 4 weeks later. In situ hybridization revealed marked and dynamic changes of GFRalpha2 mRNA levels in several forebrain areas following the stimulus-evoked seizures. Our findings provide evidence that signaling through the GFRalpha2 receptor contributes to seizure generalization in rapid kindling.

Bioreactor Transient Exposure Activates Specific Neurotrophic Pathway in Cortical Neurons

NASA Astrophysics Data System (ADS)

Zimmitti, V.; Benedetti, E.; Caracciolo, V.; Sebastiani, P.; Di Loreto, S.

2010-02-01

Altered gravity forces might influence neuroplasticity and can provoke changes in biochemical mechanisms. In this contest, neurotrophins have a pivotal role, particularly nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF). A suspension of dissociated cortical cells from rat embryos was exposed to 24 h of microgravity before plating in normal adherent culture system. Expression and transductional signalling pathways of NGF and BDNF were assessed at the end of maturational process (8-10 days in vitro). Rotating wall vessel bioreactor (RWV) pre-exposition did not induce changes in NGF expression and its high affinity receptor TrkA. On the contrary both BDNF expression and its high affinity receptor TrkB were strongly up-regulated, inducing Erk-5, but not Erk-1/2 activation and, in turn, MEF2C over-expression and activation. According to our previous and present results, we postulate that relatively short microgravitational stimuli, applied to neural cells during the developmental stage, exert a long time activation of specific neurotrophic pathways.

The marine alga Gelidium amansii promotes the development and complexity of neuronal cytoarchitecture.

PubMed

Hannan, Abdul; Kang, Ji-Young; Hong, Yong-Ki; Lee, Hyunsook; Choi, Jae-Suk; Choi, In Soon; Moon, Il Soo

2013-01-01

Neurotrophic factors are vital not only to support neuronal development but also to protect mature neurons from atrophy in neurodegenerative diseases. As an effort to explore natural sources that possess neurotrophic activity, we screened common marine algae for their neuritogenic activity in the developing rat hippocampal neurons in culture. Of the 22 seaweed species examined, ethanol extracts of Gelidium amansii (GAE) exhibited potent neuritogenic activity, followed by Undaria pinnatifida and Sargassum fulvellum extracts. The effects of GAE were dose dependent with an optimum concentration of 15 µg/mL. The GAE significantly promoted the initial neuronal differentiation from the stage I into the stage II and increased the indices of axonal and dendritic development such as the length, the numbers of primary processes, and branching frequencies by a minimum of twofold compared with the vehicle control. These results show that marine algae are promising candidates for neurotrophic potentials. Copyright © 2012 John Wiley & Sons, Ltd.

Observed parenting behaviors interact with a polymorphism of the brain-derived neurotrophic factor gene to predict the emergence of oppositional defiant and callous-unemotional behaviors at age 3 years.

PubMed

Willoughby, Michael T; Mills-Koonce, Roger; Propper, Cathi B; Waschbusch, Daniel A

2013-11-01

Using the Durham Child Health and Development Study, this study (N = 171) tested whether observed parenting behaviors in infancy (6 and 12 months) and toddlerhood/preschool (24 and 36 months) interacted with a child polymorphism of the brain-derived neurotrophic factor gene to predict oppositional defiant disorder (ODD) and callous-unemotional (CU) behaviors at age 3 years. Child genotype interacted with observed harsh and intrusive (but not sensitive) parenting to predict ODD and CU behaviors. Harsh-intrusive parenting was more strongly associated with ODD and CU for children with a methionine allele of the brain-derived neurotrophic factor gene. CU behaviors were uniquely predicted by harsh-intrusive parenting in infancy, whereas ODD behaviors were predicted by harsh-intrusive parenting in both infancy and toddlerhood/preschool. The results are discussed from the perspective of the contributions of caregiving behaviors as contributing to distinct aspects of early onset disruptive behavior.

Is Perineural Invasion of Head and Neck Squamous Cell Carcinomas Linked to Tobacco Consumption?

PubMed

Baumeister, Philipp; Welz, Christian; Jacobi, Christian; Reiter, Maximilian

2018-05-01

Perineural invasion (PNI) is an underrecognized path of cancer spread, and its causes and mechanisms are poorly understood. Recent research indicates a mutual attraction of neuronal and cancer cells, largely dependent on neurotrophic factors and their receptors. Interestingly, the release of neurotrophic factors occurs upon cigarette smoke/nicotine exposure in a dose-dependent manner, and serum levels correlate with current smoking, number of smoking years, and smoking severity. Among cell types capable of neurotrophic factors secretion are lung and oral fibroblasts. In our study of 178 patients with head and neck squamous cell carcinoma, tumors of current and former smokers showed PNI significantly more often than tumors of never smokers. Moreover, PNI was a marker for aggressive tumor growth. Surprisingly, PNI was more significant for survival than p16 status. Our study warrants further research on PNI in head and neck squamous cell carcinoma with special emphasis on the impact of tobacco consumption to identify suitable candidates for therapeutic interventions.

Brain-derived neurotrophic factor Val66Met polymorphism and dexamethasone/CRH test results in depressed patients.

PubMed

Schüle, Cornelius; Zill, Peter; Baghai, Thomas C; Eser, Daniela; Zwanzger, Peter; Wenig, Nadine; Rupprecht, Rainer; Bondy, Brigitta

2006-09-01

Data suggest that both neurotrophic and hypothalamic-pituitary-adrenocortical (HPA) systems are involved in the pathophysiology of depression. The aim of the present study was to investigate whether the non-conservative brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has an impact on HPA axis activity in depressed patients. At admission, the dexamethasone/CRH (DEX/CRH) test was performed in 187 drug-free in-patients suffering from major depression or depressed state of bipolar disorder (DSM-IV criteria). Moreover, genotyping of BDNF Val66Met polymorphism was carried out using the fluorescence resonance energy transfer method (FRET). Homozygous carriers of the Met/Met genotype showed a significantly higher HPA axis activity during the DEX/CRH test than patients carrying the Val/Val or Val/Met genotype (ACTH, cortisol). Our results further contribute to the hypothesized association between HPA axis dysregulation and reduced neuroplasticity in depression and are consistent with the assumption that BDNF is a stress-responsive intercellular messenger modifying HPA axis activity.

From Molecular to Nanotechnology Strategies for Delivery of Neurotrophins: Emphasis on Brain-Derived Neurotrophic Factor (BDNF)

PubMed Central

Géral, Claire; Angelova, Angelina; Lesieur, Sylviane

2013-01-01

Neurodegenerative diseases represent a major public health problem, but beneficial clinical treatment with neurotrophic factors has not been established yet. The therapeutic use of neurotrophins has been restrained by their instability and rapid degradation in biological medium. A variety of strategies has been proposed for the administration of these leading therapeutic candidates, which are essential for the development, survival and function of human neurons. In this review, we describe the existing approaches for delivery of brain-derived neurotrophic factor (BDNF), which is the most abundant neurotrophin in the mammalian central nervous system (CNS). Biomimetic peptides of BDNF have emerged as a promising therapy against neurodegenerative disorders. Polymer-based carriers have provided sustained neurotrophin delivery, whereas lipid-based particles have contributed also to potentiation of the BDNF action. Nanotechnology offers new possibilities for the design of vehicles for neuroprotection and neuroregeneration. Recent developments in nanoscale carriers for encapsulation and transport of BDNF are highlighted. PMID:24300402

Brain-Derived Neurotrophic Factor in Alzheimer's Disease: Risk, Mechanisms, and Therapy.

PubMed

Song, Jing-Hui; Yu, Jin-Tai; Tan, Lan

2015-12-01

Brain-derived neurotrophic factor (BDNF) has a neurotrophic support on neuron of central nervous system (CNS) and is a key molecule in the maintenance of synaptic plasticity and memory storage in hippocampus. However, changes of BDNF level and expression have been reported in the CNS as well as blood of Alzheimer's disease (AD) patients in the last decade, which indicates a potential role of BDNF in the pathogenesis of AD. Therefore, this review aims to summarize the latest progress in the field of BDNF and its biological roles in AD pathogenesis. We will discuss the interaction between BDNF and amyloid beta (Aβ) peptide, the effect of BDNF on synaptic repair in AD, and the association between BDNF polymorphism and AD risk. The most important is, enlightening the detailed biological ability and complicated mechanisms of action of BDNF in the context of AD would provide a future BDNF-related remedy for AD, such as increment in the production or release of endogenous BDNF by some drugs or BDNF mimics.

A needs assessment of health information technology for improving care coordination in three leading patient-centered medical homes.

PubMed

Richardson, Joshua E; Vest, Joshua R; Green, Cori M; Kern, Lisa M; Kaushal, Rainu

2015-07-01

We investigated ways that patient-centered medical homes (PCMHs) are currently using health information technology (IT) for care coordination and what types of health IT are needed to improve care coordination. A multi-disciplinary team of researchers conducted semi-structured telephone interviews with 28 participants from 3 PCMHs in the United States. Participants included administrators and clinicians from PCMHs, electronic health record (EHR) and health information exchange (HIE) representatives, and policy makers. Participants identified multiple barriers to care coordination using current health IT tools. We identified five areas in which health IT can improve care coordination in PCMHs: 1) monitoring patient populations, 2) notifying clinicians and other staff when specific patients move across care settings, 3) collaborating around patients, 4) reporting activities, and 5) interoperability. To accomplish these tasks, many participants described using homegrown care coordination systems separate from EHRs. The participants in this study have resources, experience, and expertise with using health IT for care coordination, yet they still identified multiple areas for improvement. We hypothesize that focusing health IT development in the five areas we identified can enable more effective care coordination. Key findings from this work are that homegrown systems apart from EHRs are currently used to support care coordination and, also, that reporting tools are key components of care coordination. New health IT that enables monitoring, notifying, collaborating, reporting, and interoperability would enhance care coordination within PCMHs beyond what current health IT enables. © The Author 2015. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Association Between Brain-Derived Neurotrophic Factor Genotype and Upper Extremity Motor Outcome After Stroke.

PubMed

Chang, Won Hyuk; Park, Eunhee; Lee, Jungsoo; Lee, Ahee; Kim, Yun-Hee

2017-06-01

The identification of intrinsic factors for predicting upper extremity motor outcome could aid the design of individualized treatment plans in stroke rehabilitation. The aim of this study was to identify prognostic factors, including intrinsic genetic factors, for upper extremity motor outcome in patients with subacute stroke. A total of 97 patients with subacute stroke were enrolled. Upper limb motor impairment was scored according to the upper limb of Fugl-Meyer assessment score at 3 months after stroke. The prediction of upper extremity motor outcome at 3 months was modeled using various factors that could potentially influence this impairment, including patient characteristics, baseline upper extremity motor impairment, functional and structural integrity of the corticospinal tract, and brain-derived neurotrophic factor genotype. Multivariate ordinal logistic regression models were used to identify the significance of each factor. The independent predictors of motor outcome at 3 months were baseline upper extremity motor impairment, age, stroke type, and corticospinal tract functional integrity in all stroke patients. However, in the group with severe motor impairment at baseline (upper limb score of Fugl-Meyer assessment <25), the number of Met alleles in the brain-derived neurotrophic factor genotype was also an independent predictor of upper extremity motor outcome 3 months after stroke. Brain-derived neurotrophic factor genotype may be a potentially useful predictor of upper extremity motor outcome in patients with subacute stroke with severe baseline motor involvement. © 2017 American Heart Association, Inc.

Neurotrophic requirements of human motor neurons defined using amplified and purified stem cell-derived cultures.

PubMed

Lamas, Nuno Jorge; Johnson-Kerner, Bethany; Roybon, Laurent; Kim, Yoon A; Garcia-Diaz, Alejandro; Wichterle, Hynek; Henderson, Christopher E

2014-01-01

Human motor neurons derived from embryonic and induced pluripotent stem cells (hESCs and hiPSCs) are a potentially important tool for studying motor neuron survival and pathological cell death. However, their basic survival requirements remain poorly characterized. Here, we sought to optimize a robust survival assay and characterize their response to different neurotrophic factors. First, to increase motor neuron yield, we screened a small-molecule collection and found that the Rho-associated kinase (ROCK) inhibitor Y-27632 enhances motor neuron progenitor proliferation up to 4-fold in hESC and hiPSC cultures. Next, we FACS-purified motor neurons expressing the Hb9::GFP reporter from Y-27632-amplified embryoid bodies and cultured them in the presence of mitotic inhibitors to eliminate dividing progenitors. Survival of these purified motor neurons in the absence of any other cell type was strongly dependent on neurotrophic support. GDNF, BDNF and CNTF all showed potent survival effects (EC(50) 1-2 pM). The number of surviving motor neurons was further enhanced in the presence of forskolin and IBMX, agents that increase endogenous cAMP levels. As a demonstration of the ability of the assay to detect novel neurotrophic agents, Y-27632 itself was found to support human motor neuron survival. Thus, purified human stem cell-derived motor neurons show survival requirements similar to those of primary rodent motor neurons and can be used for rigorous cell-based screening.

Neurotrophic Requirements of Human Motor Neurons Defined Using Amplified and Purified Stem Cell-Derived Cultures

PubMed Central

Lamas, Nuno Jorge; Johnson-Kerner, Bethany; Roybon, Laurent; Kim, Yoon A.; Garcia-Diaz, Alejandro; Wichterle, Hynek; Henderson, Christopher E.

2014-01-01

Human motor neurons derived from embryonic and induced pluripotent stem cells (hESCs and hiPSCs) are a potentially important tool for studying motor neuron survival and pathological cell death. However, their basic survival requirements remain poorly characterized. Here, we sought to optimize a robust survival assay and characterize their response to different neurotrophic factors. First, to increase motor neuron yield, we screened a small-molecule collection and found that the Rho-associated kinase (ROCK) inhibitor Y-27632 enhances motor neuron progenitor proliferation up to 4-fold in hESC and hiPSC cultures. Next, we FACS-purified motor neurons expressing the Hb9::GFP reporter from Y-27632-amplified embryoid bodies and cultured them in the presence of mitotic inhibitors to eliminate dividing progenitors. Survival of these purified motor neurons in the absence of any other cell type was strongly dependent on neurotrophic support. GDNF, BDNF and CNTF all showed potent survival effects (EC50 1–2 pM). The number of surviving motor neurons was further enhanced in the presence of forskolin and IBMX, agents that increase endogenous cAMP levels. As a demonstration of the ability of the assay to detect novel neurotrophic agents, Y-27632 itself was found to support human motor neuron survival. Thus, purified human stem cell-derived motor neurons show survival requirements similar to those of primary rodent motor neurons and can be used for rigorous cell-based screening. PMID:25337699

Long non-coding RNA nuclear paraspeckle assembly transcript 1 inhibits the apoptosis of retina Müller cells after diabetic retinopathy through regulating miR-497/brain-derived neurotrophic factor axis.

PubMed

Li, Xiu-Juan

2018-05-01

The role of long non-coding RNA in diabetic retinopathy, a serious complication of diabetes mellitus, has attracted increasing attention in recent years. The purpose of this study was to explore whether long non-coding RNA nuclear paraspeckle assembly transcript 1 was involved in the context of diabetic retinopathy and its underlying mechanisms. Our results revealed that nuclear paraspeckle assembly transcript 1 was significantly downregulated in the retina of diabetes mellitus rats. Meanwhile, miR-497 was significantly increased in diabetes mellitus rats' retina and high glucose-treated Müller cells, but brain-derived neurotrophic factor was increased. We also found that high glucose-induced apoptosis of Müller cells was accompanied by the significant downregulation of nuclear paraspeckle assembly transcript 1 in vitro. Further study demonstrated that high glucose-promoted Müller cells apoptosis through downregulating nuclear paraspeckle assembly transcript 1 and downregulated nuclear paraspeckle assembly transcript 1 mediated this effect via negative regulating miR-497. Moreover, brain-derived neurotrophic factor was negatively regulated by miR-497 and associated with the apoptosis of Müller cells under high glucose. Our results suggested that under diabetic conditions, downregulated nuclear paraspeckle assembly transcript 1 decreased the expression of brain-derived neurotrophic factor through elevating miR-497, thereby promoting Müller cells apoptosis and aggravating diabetic retinopathy.

Tyrosine receptor kinase B receptor activation reverses the impairing effects of acute nicotine on contextual fear extinction.

PubMed

Kutlu, Munir Gunes; Cole, Robert D; Connor, David A; Natwora, Brendan; Gould, Thomas J

2018-03-01

Anxiety and stress disorders have been linked to deficits in fear extinction. Our laboratory and others have demonstrated that acute nicotine impairs contextual fear extinction, suggesting that nicotine exposure may have negative effects on anxiety and stress disorder symptomatology. However, the neurobiological mechanisms underlying the acute nicotine-induced impairment of contextual fear extinction are unknown. Therefore, based on the previous studies showing that brain-derived neurotrophic factor is central for fear extinction learning and acute nicotine dysregulates brain-derived neurotrophic factor signaling, we hypothesized that the nicotine-induced impairment of contextual fear extinction may involve changes in tyrosine receptor kinase B signaling. To test this hypothesis, we systemically, intraperitoneally, injected C57BL/6J mice sub-threshold doses (2.5 and 4.0 mg/kg) of 7,8-dihydroxyflavone, a small-molecule tyrosine receptor kinase B agonist that fully mimics the effects of brain-derived neurotrophic factor, or vehicle an hour before each contextual fear extinction session. Mice also received injections, intraperitoneally, of acute nicotine (0.18 mg/kg) or saline 2-4 min before extinction sessions. While the animals that received only 7,8-dihydroxyflavone did not show any changes in contextual fear extinction, 4.0 mg/kg of 7,8-dihydroxyflavone ameliorated the extinction deficits in mice administered acute nicotine. Overall, these results suggest that acute nicotine-induced impairment of context extinction may be related to a disrupted brain-derived neurotrophic factor signaling.

A Lyapunov-based Approach for Time-Coordinated 3D Path-Following of Multiple Quadrotors in SO(3)

DTIC Science & Technology

2012-12-10

January 2006. [22] T. Lee, “ Robust adaptive geometric tracking controls on so(3) with an application to the attitude dynamicsof a quadrotor uav,” 2011...in the presence of time-varying communication networks and spatial and temporal constraints. The objective is to enable n Quadrotors to track prede?ned...developing control laws to solve the Time-Coordinated 3D Path-Following task for multiple Quadrotor UAVs in the presence of time-varying communication

Strike-parallel and strike-normal coordinate system around geometrically complicated rupture traces: use by NGA-West2 and further improvements

USGS Publications Warehouse

Spudich, Paul A.; Chiou, Brian

2015-01-01

We present a two-dimensional system of generalized coordinates for use with geometrically complex fault ruptures that are neither straight nor continuous. The coordinates are a generalization of the conventional strike-normal and strike-parallel coordinates of a single straight fault. The presented conventions and formulations are applicable to a single curved trace, as well as multiple traces representing the rupture of branching faults or noncontiguous faults. An early application of our generalized system is in the second round of the Next Generation of Ground-Motion Attenuation Model project for the Western United States (NGA-West2), where they were used in the characterization of the hanging-wall effects. We further improve the NGA-West2 strike-parallel formulation for multiple rupture traces with a more intuitive definition of the nominal strike direction. We also derive an analytical expression for the gradient of the generalized strike-normal coordinate. The direction of this gradient may be used as the strike-normal direction in the study of polarization effects on ground motions.

The active site structure of tetanus neurotoxin resolved by multiple scattering analysis in X-Ray absorption spectroscopy.

PubMed Central

Meneghini, C; Morante, S

1998-01-01

A detailed study of the x-ray absorption spectrum of tetanus neurotoxin in the K-edge EXAFS region of the zinc absorber is presented that allows the complete identification of the amino acid residues coordinated to the zinc active site. A very satisfactory interpretation of the experimental data can be given if multiple scattering contributions are included in the analysis. Comparing the absorption spectrum of tetanus neurotoxin to that of two other structurally similar zinc-endopeptidases, thermolysin and astacin, in which the zinc coordination mode is known from crystallographic data, we conclude that in tetanus neurotoxin, besides a water molecule, zinc is coordinated to two histidines and a tyrosine. PMID:9746536

Neural-adaptive control of single-master-multiple-slaves teleoperation for coordinated multiple mobile manipulators with time-varying communication delays and input uncertainties.

PubMed

Li, Zhijun; Su, Chun-Yi

2013-09-01

In this paper, adaptive neural network control is investigated for single-master-multiple-slaves teleoperation in consideration of time delays and input dead-zone uncertainties for multiple mobile manipulators carrying a common object in a cooperative manner. Firstly, concise dynamics of teleoperation systems consisting of a single master robot, multiple coordinated slave robots, and the object are developed in the task space. To handle asymmetric time-varying delays in communication channels and unknown asymmetric input dead zones, the nonlinear dynamics of the teleoperation system are transformed into two subsystems through feedback linearization: local master or slave dynamics including the unknown input dead zones and delayed dynamics for the purpose of synchronization. Then, a model reference neural network control strategy based on linear matrix inequalities (LMI) and adaptive techniques is proposed. The developed control approach ensures that the defined tracking errors converge to zero whereas the coordination internal force errors remain bounded and can be made arbitrarily small. Throughout this paper, stability analysis is performed via explicit Lyapunov techniques under specific LMI conditions. The proposed adaptive neural network control scheme is robust against motion disturbances, parametric uncertainties, time-varying delays, and input dead zones, which is validated by simulation studies.

Controversies about a common etiology for eating and mood disorders

PubMed Central

Rossetti, Clara; Halfon, Olivier; Boutrel, Benjamin

2014-01-01

Obesity and depression represent a growing health concern worldwide. For many years, basic science and medicine have considered obesity as a metabolic illness, while depression was classified a psychiatric disorder. Despite accumulating evidence suggesting that obesity and depression may share commonalities, the causal link between eating and mood disorders remains to be fully understood. This etiology is highly complex, consisting of multiple environmental and genetic risk factors that interact with each other. In this review, we sought to summarize the preclinical and clinical evidence supporting a common etiology for eating and mood disorders, with a particular emphasis on signaling pathways involved in the maintenance of energy balance and mood stability, among which orexigenic and anorexigenic neuropeptides, metabolic factors, stress responsive hormones, cytokines, and neurotrophic factors. PMID:25386150

Multiple Sensor Platform Coordination Using Stigmergy

DTIC Science & Technology

1998-03-01

French biologist P.P. Grass`e in 1959 while studying nest building of termites . He observed that indirect coordination among termites was accomplished...through sensing and modification of their environment. The chemicals secreted by each termite during nest building affected the building actions of...neighboring termites , resulting in a coordinated building strategy. Stigmergy is not limited to termites . Some species of ants use stigmergy for trail

Blastema induction in aneurogenic state and Prrx-1 regulation by MMPs and FGFs in Ambystoma mexicanum limb regeneration.

PubMed

Satoh, Akira; makanae, Aki; Hirata, Ayako; Satou, Yutaka

2011-07-15

Urodele amphibians can regenerate amputated limbs. It has been considered that differentiated dermal tissues generate multipotent and undifferentiated cells called blastema cells during limb regeneration. In early phases of limb regeneration, blastema cells are induced by nerves and the apical epithelial cap (AEC). We had previously investigated the role of neurotrophic factors in blastema or blastema-like formation consisting of Prrx-1 positive cells. A new system suitable for investigating early phases of limb regeneration, called the accessory limb model (ALM), was recently developed. In this study, we performed a comparative transcriptome analysis between a blastema and wound using ALM. Matrix metalloproteinase (MMP) and fibroblast growth factor (FGF) signaling components were observed to be predominantly expressed in ALM blastema cells. Furthermore, we found that MMP activity induced a blastema marker gene, Prrx-1, in vitro, and FGF signaling pathways worked in coordination to maintain Prrx-1 expression and ALM blastema formation. Furthermore, we demonstrated that these two activities were sufficient to induce an ALM blastema in the absence of a nerve in vivo. Copyright © 2011 Elsevier Inc. All rights reserved.

Effect of childhood maltreatment and brain-derived neurotrophic factor on brain morphology.

PubMed

van Velzen, Laura S; Schmaal, Lianne; Jansen, Rick; Milaneschi, Yuri; Opmeer, Esther M; Elzinga, Bernet M; van der Wee, Nic J A; Veltman, Dick J; Penninx, Brenda W J H

2016-11-01

Childhood maltreatment (CM) has been associated with altered brain morphology, which may partly be due to a direct impact on neural growth, e.g. through the brain-derived neurotrophic factor (BDNF) pathway. Findings on CM, BDNF and brain volume are inconsistent and have never accounted for the entire BDNF pathway. We examined the effects of CM, BDNF (genotype, gene expression and protein level) and their interactions on hippocampus, amygdala and anterior cingulate cortex (ACC) morphology. Data were collected from patients with depression and/or an anxiety disorder and healthy subjects within the Netherlands Study of Depression and Anxiety (NESDA) (N = 289). CM was assessed using the Childhood Trauma Interview. BDNF Val66Met genotype, gene expression and serum protein levels were determined in blood and T1 MRI scans were acquired at 3T. Regional brain morphology was assessed using FreeSurfer. Covariate-adjusted linear regression analyses were performed. Amygdala volume was lower in maltreated individuals. This was more pronounced in maltreated met-allele carriers. The expected positive relationship between BDNF gene expression and volume of the amygdala is attenuated in maltreated subjects. Finally, decreased cortical thickness of the ACC was identified in maltreated subjects with the val/val genotype. CM was associated with altered brain morphology, partly in interaction with multiple levels of the BNDF pathway. Our results suggest that CM has different effects on brain morphology in met-carriers and val-homozygotes and that CM may disrupt the neuroprotective effect of BDNF. © The Author (2016). Published by Oxford University Press.

Sodium Benzoate, a Metabolite of Cinnamon and a Food Additive, Upregulates Ciliary Neurotrophic Factor in Astrocytes and Oligodendrocytes.

PubMed

Modi, Khushbu K; Jana, Malabendu; Mondal, Susanta; Pahan, Kalipada

2015-11-01

Ciliary neurotrophic factor (CNTF) is a promyelinating trophic factor that plays an important role in multiple sclerosis (MS). However, mechanisms by which CNTF expression could be increased in the brain are poorly understood. Recently we have discovered anti-inflammatory and immunomodulatory activities of sodium benzoate (NaB), a metabolite of cinnamon and a widely-used food additive. Here, we delineate that NaB is also capable of increasing the mRNA and protein expression of CNTF in primary mouse astrocytes and oligodendrocytes and primary human astrocytes. Accordingly, oral administration of NaB and cinnamon led to the upregulation of astroglial and oligodendroglial CNTF in vivo in mouse brain. Induction of experimental allergic encephalomyelitis, an animal model of MS, reduced the level of CNTF in the brain, which was restored by oral administration of cinnamon. While investigating underlying mechanisms, we observed that NaB induced the activation of protein kinase A (PKA) and H-89, an inhibitor of PKA, abrogated NaB-induced expression of CNTF. The activation of cAMP response element binding (CREB) protein by NaB, the recruitment of CREB and CREB-binding protein to the CNTF promoter by NaB and the abrogation of NaB-induced expression of CNTF in astrocytes by siRNA knockdown of CREB suggest that NaB increases the expression of CNTF via the activation of CREB. These results highlight a novel myelinogenic property of NaB and cinnamon, which may be of benefit for MS and other demyelinating disorders.

An update-tissue engineered nerve grafts for the repair of peripheral nerve injuries.

PubMed

Patel, Nitesh P; Lyon, Kristopher A; Huang, Jason H

2018-05-01

Peripheral nerve injuries (PNI) are caused by a range of etiologies and result in a broad spectrum of disability. While nerve autografts are the current gold standard for the reconstruction of extensive nerve damage, the limited supply of autologous nerve and complications associated with harvesting nerve from a second surgical site has driven groups from multiple disciplines, including biomedical engineering, neurosurgery, plastic surgery, and orthopedic surgery, to develop a suitable or superior alternative to autografting. Over the last couple of decades, various types of scaffolds, such as acellular nerve grafts (ANGs), nerve guidance conduits, and non-nervous tissues, have been filled with Schwann cells, stem cells, and/or neurotrophic factors to develop tissue engineered nerve grafts (TENGs). Although these have shown promising effects on peripheral nerve regeneration in experimental models, the autograft has remained the gold standard for large nerve gaps. This review provides a discussion of recent advances in the development of TENGs and their efficacy in experimental models. Specifically, TENGs have been enhanced via incorporation of genetically engineered cells, methods to improve stem cell survival and differentiation, optimized delivery of neurotrophic factors via drug delivery systems (DDS), co-administration of platelet-rich plasma (PRP), and pretreatment with chondroitinase ABC (Ch-ABC). Other notable advancements include conduits that have been bioengineered to mimic native nerve structure via cell-derived extracellular matrix (ECM) deposition, and the development of transplantable living nervous tissue constructs from rat and human dorsal root ganglia (DRG) neurons. Grafts composed of non-nervous tissues, such as vein, artery, and muscle, will be briefly discussed.

Coordinated Science Campaign Scheduling for Sensor Webs

NASA Technical Reports Server (NTRS)

Edgington, Will; Morris, Robert; Dungan, Jennifer; Williams, Jenny; Carlson, Jean; Fleming, Damian; Wood, Terri; Yorke-Smith, Neil

2005-01-01

Future Earth observing missions will study different aspects and interacting pieces of the Earth's eco-system. Scientists are designing increasingly complex, interdisciplinary campaigns to exploit the diverse capabilities of multiple Earth sensing assets. In addition, spacecraft platforms are being configured into clusters, trains, or other distributed organizations in order to improve either the quality or the coverage of observations. These simultaneous advances in the design of science campaigns and in the missions that will provide the sensing resources to support them offer new challenges in the coordination of data and operations that are not addressed by current practice. For example, the scheduling of scientific observations for satellites in low Earth orbit is currently conducted independently by each mission operations center. An absence of an information infrastructure to enable the scheduling of coordinated observations involving multiple sensors makes it difficult to execute campaigns involving multiple assets. This paper proposes a software architecture and describes a prototype system called DESOPS (Distributed Earth Science Observation Planning and Scheduling) that will address this deficiency.

The gene coding for glial cell line derived neurotrophic factor (GDNF) maps to chromosome 5p12-p13.1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schindelhauer, D.; Schuffenhauer, S.; Meitinger, T.

1995-08-10

The gene coding for glial cell line derived neurotrophic factor (GDNF) has biological properties that may have potential as a treatment for Parkinson`s and motoneuron diseases. Using the NIGMS Mapping Panel 2, we have localized the GDNF gene to human chromosome 5p12-p13.1. Large NruI and NotI fragments on chromosome 5 will facilitate the construction of a long-range map of the region. 26 refs., 1 fig., 1 tab.

Movement coordination patterns between the foot joints during walking.

PubMed

Arnold, John B; Caravaggi, Paolo; Fraysse, François; Thewlis, Dominic; Leardini, Alberto

2017-01-01

In 3D gait analysis, kinematics of the foot joints are usually reported via isolated time histories of joint rotations and no information is provided on the relationship between rotations at different joints. The aim of this study was to identify movement coordination patterns in the foot during walking by expanding an existing vector coding technique according to an established multi-segment foot and ankle model. A graphical representation is also described to summarise the coordination patterns of joint rotations across multiple patients. Three-dimensional multi-segment foot kinematics were recorded in 13 adults during walking. A modified vector coding technique was used to identify coordination patterns between foot joints involving calcaneus, midfoot, metatarsus and hallux segments. According to the type and direction of joints rotations, these were classified as in-phase (same direction), anti-phase (opposite directions), proximal or distal joint dominant. In early stance, 51 to 75% of walking trials showed proximal-phase coordination between foot joints comprising the calcaneus, midfoot and metatarsus. In-phase coordination was more prominent in late stance, reflecting synergy in the simultaneous inversion occurring at multiple foot joints. Conversely, a distal-phase coordination pattern was identified for sagittal plane motion of the ankle relative to the midtarsal joint, highlighting the critical role of arch shortening to locomotor function in push-off. This study has identified coordination patterns between movement of the calcaneus, midfoot, metatarsus and hallux by expanding an existing vector cording technique for assessing and classifying coordination patterns of foot joints rotations during walking. This approach provides a different perspective in the analysis of multi-segment foot kinematics, and may be used for the objective quantification of the alterations in foot joint coordination patterns due to lower limb pathologies or following injuries.

Tools for Coordinated Planning Between Observatories

NASA Technical Reports Server (NTRS)

Jones, Jeremy; Fishman, Mark; Grella, Vince; Kerbel, Uri; Maks, Lori; Misra, Dharitri; Pell, Vince; Powers, Edward I. (Technical Monitor)

2001-01-01

With the realization of NASA's era of great observatories, there are now more than three space-based telescopes operating in different wavebands. This situation provides astronomers with a unique opportunity to simultaneously observe with multiple observatories. Yet scheduling multiple observatories simultaneously is highly inefficient when compared to observations using only one single observatory. Thus, programs using multiple observatories are limited not due to scientific restrictions, but due to operational inefficiencies. At present, multi-observatory programs are conducted by submitting observing proposals separately to each concerned observatory. To assure that the proposed observations can be scheduled, each observatory's staff has to check that the observations are valid and meet all the constraints for their own observatory; in addition, they have to verify that the observations satisfy the constraints of the other observatories. Thus, coordinated observations require painstaking manual collaboration among the observatory staff at each observatory. Due to the lack of automated tools for coordinated observations, this process is time consuming, error-prone, and the outcome of the requests is not certain until the very end. To increase observatory operations efficiency, such manpower intensive processes need to undergo re-engineering. To overcome this critical deficiency, Goddard Space Flight Center's Advanced Architectures and Automation Branch is developing a prototype effort called the Visual Observation Layout Tool (VOLT). The main objective of the VOLT project is to provide visual tools to help automate the planning of coordinated observations by multiple astronomical observatories, as well as to increase the scheduling probability of all observations.

Coordinated neuronal activity enhances corticocortical communication

PubMed Central

Zandvakili, Amin; Kohn, Adam

2015-01-01

Summary Relaying neural signals between cortical areas is central to cognition and sensory processing. The temporal coordination of activity in a source population has been suggested to determine corticocortical signaling efficacy, but others have argued that coordination is functionally irrelevant. We reasoned that if coordination significantly influenced signaling, spiking in downstream networks should be preceded by transiently elevated coordination in a source population. We developed a metric to quantify network coordination in brief epochs, and applied it to simultaneous recordings of neuronal populations in cortical areas V1 and V2 of the macaque monkey. Spiking in the input layers of V2 was preceded by brief epochs of elevated V1 coordination, but this was not the case in other layers of V2. Our results indicate that V1 coordination influences its signaling to direct downstream targets, but that coordinated V1 epochs do not propagate through multiple downstream networks as in some corticocortical signaling schemes. PMID:26291164

N-acetylcysteine (NAC) in neurological disorders: mechanisms of action and therapeutic opportunities

PubMed Central

Bavarsad Shahripour, Reza; Harrigan, Mark R; Alexandrov, Andrei V

2014-01-01

Background There is an expanding field of research investigating the benefits of medicines with multiple mechanisms of action across neurological disorders. N-acetylcysteine (NAC), widely known as an antidote to acetaminophen overdose, is now emerging as treatment of vascular and nonvascular neurological disorders. NAC as a precursor to the antioxidant glutathione modulates glutamatergic, neurotrophic, and inflammatory pathways. Aim and discussion Most NAC studies up to date have been carried out in animal models of various neurological disorders with only a few studies completed in humans. In psychiatry, NAC has been tested in over 20 clinical trials as an adjunctive treatment; however, this topic is beyond the scope of this review. Herein, we discuss NAC molecular, intracellular, and systemic effects, focusing on its potential applications in neurodegenerative diseases including spinocerebellar ataxia, Parkinson's disease, tardive dyskinesia, myoclonus epilepsy of the Unverricht–Lundbor type as well as multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease. Conclusion Finally, we review the potential applications of NAC to facilitate recovery after traumatic brain injury, cerebral ischemia, and in treatment of cerebrovascular vasospasm after subarachnoid hemorrhage. PMID:24683506

Calibration method for video and radiation imagers

DOEpatents

Cunningham, Mark F [Oak Ridge, TN; Fabris, Lorenzo [Knoxville, TN; Gee, Timothy F [Oak Ridge, TN; Goddard, Jr., James S.; Karnowski, Thomas P [Knoxville, TN; Ziock, Klaus-peter [Clinton, TN

2011-07-05

The relationship between the high energy radiation imager pixel (HERIP) coordinate and real-world x-coordinate is determined by a least square fit between the HERIP x-coordinate and the measured real-world x-coordinates of calibration markers that emit high energy radiation imager and reflect visible light. Upon calibration, a high energy radiation imager pixel position may be determined based on a real-world coordinate of a moving vehicle. Further, a scale parameter for said high energy radiation imager may be determined based on the real-world coordinate. The scale parameter depends on the y-coordinate of the moving vehicle as provided by a visible light camera. The high energy radiation imager may be employed to detect radiation from moving vehicles in multiple lanes, which correspondingly have different distances to the high energy radiation imager.

Enhancing healthcare sector coordination through infrastructure and logistics support.

PubMed

Zoraster, Richard M

2010-01-01

The International Response to the 2004 Southeast Asia Tsunami was noted to have multiple areas of poor coordination, and in 2005, the "Health Cluster"approach to coordination was formulated. However, the 2010 Haiti response suggests that many of the same problems continue and that there are significant limitations to the cluster meetings. These limitations include the inconsistent attendance, poor dissemination of information, and perceived lack of benefit to providers. This article proposes that healthcare coordination would be greatly improved with logistical support, leading to improved efficiency and outcomes for those affected by disasters.

Do Unilateral Herpetic Stromal Keratitis and Neurotrophic Ulcers Cause Bilateral Dry Eye?

PubMed

Jabbarvand, Mahmoud; Hashemian, Hesam; Khodaparast, Mehdi; Rafatnejad, Amin; Beheshtnejad, Amirhooshang; Salami, Amir

2015-07-01

To evaluate and compare the ocular surface condition in herpetic interstitial stromal keratitis and neurotrophic ulcer groups and their normal fellow eyes. In this observational, cross-sectional case-control study, 85 consecutive patients were included, including 56 cases of treated herpetic interstitial keratitis and 29 patients with neurotrophic ulcers. Fifty-six age- and sex-matched participants were also recruited from a normal population as the control group. We evaluated and scored the subjective and objective measures of dry eye for both eyes of all patients. Then, we compared the score of the groups with one another and also with the control group. The main outcome measures were the discomfort level, visual symptoms of dry eye, conjunctival injection, conjunctival staining, corneal staining, corneal tear signs of dry eye, meibomian gland dysfunction, tear break-up time, Schirmer test score with anesthesia, and tear osmolarity. The normal fellow eye of the herpetic keratitis group had significantly higher discomfort levels (1.4 ± 0.9 vs. 1.3 ± 0.5, P = 0.003), visual symptoms (1.7 ± 0.8 vs. 1.3 ± 0.7, P = 0.002), tear break-up time (8.3 ± 3.2 vs. 12.1 ± 3.3 seconds, P = 0.003), Schirmer test scores (9.2 ± 3.9 vs. 12.9 ± 3 mm, P = 0.04), and tear osmolarity (9.2 ± 3.9 vs. 12.9 ± 3 mm, P = 0.003) in comparison with normal controls. The normal fellow eyes of the neurotrophic ulcer group had significantly worse values for discomfort level (1.9 ± 0.9 vs. 1.3 ± 0.5, P < 0.001), tear break-up time (7.9 ± 4 vs. 12.1 ± 3.3, P = 0.004), Schirmer test score (8.1 ± 3.9 vs. 12.9 ± 3, P = 0.005), and tear osmolarity (295 ± 9.2 vs. 292.7 ± 5.9, P = 0.02) compared with normal controls. Both eyes of patients with neurotrophic ulcer and interstitial herpetic keratitis have a significantly poorer ocular surface condition compared with that of normal controls.

Nootropic, neuroprotective and neurotrophic effects of phloretin in scopolamine induced amnesia in mice.

PubMed

Ghumatkar, Priya J; Patil, Sachin P; Jain, Pankaj D; Tambe, Rufi M; Sathaye, Sadhana

2015-08-01

Phloretin (PHL), a dihydrochalcone flavonoid usually present in the roots and leaves of apple tree. In vitro study on GT1-7 immortalized hypothalamic neurons exposed to amyloid beta (25-35), demonstrated that PHL significantly influenced membrane fluidity and potential. PHL also significantly decreased excitotoxicity by restoring the calcium homeostasis in the same. Thus, PHL proves to be a promising therapeutic moiety which should be further screened in the treatment of Alzheimer's disease. The objective of the present study was to evaluate the nootropic, neuroprotective and neurotrophic roles of PHL in the subacute scopolamine induced amnesia in mice. In this study, mice were pretreated with PHL 2.5mg/kg, 5mg/kg, 10mg/kg and Donepezil (DON) 1mg/kg intraperitoneally (i.p) for 14days. The last 7days of treatment regimen included daily injection of SCP 1.5mg/kg to induce cognitive deficits. Mice were subjected to behavioral analysis. Biochemical estimation of the brain homogenates for acetylcholinesterase and oxidative stress biomarkers were conducted. Furthermore, immunohistochemical analysis for the brain derived neurotrophic factor (BDNF) was carried out particularly in the hippocampus. PHL was found to significantly improve the performance of mice in Morris water maze test (P<0.001) and significantly decreased the acetylcholinesterase activity (P<0.001) at all doses compared to SCP treated mice. Also, PHL significantly elevated the activity of antioxidant enzymes viz. superoxide dismutase, catalase, reduced glutathione levels (P<0.001) and decreased malonaldehyde levels (P<0.001) in comparison with the SCP group. Immunohistochemistry revealed that PHL treatment dose dependently improved BDNF levels in the hippocampus which were found to be significantly depleted (P<0.001) in the SCP group. Additionally, PHL (10mg/kg) significantly enhanced the spatial memory formation (P<0.05) and neurotrophicity (P<0.001) compared to DON (1mg/kg). The aforementioned research findings suggested that PHL has nootropic, neuroprotective and neurotrophic activities in SCP induced memory impaired mice and hence, is a promising therapeutic moiety in the treatment of AD. Copyright © 2015 Elsevier Inc. All rights reserved.

Effect of Exercise Intensity on Neurotrophic Factors and Blood-Brain Barrier Permeability Induced by Oxidative-Nitrosative Stress in Male College Students.

PubMed

Roh, Hee-Tae; Cho, Su-Youn; Yoon, Hyung-Gi; So, Wi-Young

2017-06-01

We investigated the effects of aerobic exercise intensity on oxidative-nitrosative stress, neurotrophic factor expression, and blood-brain barrier (BBB) permeability. Fifteen healthy men performed treadmill running under low-intensity (LI), moderate-intensity (MI), and high-intensity (HI) conditions. Blood samples were collected immediately before exercise (IBE), immediately after exercise (IAE), and 60 min after exercise (60MAE) to examine oxidative-nitrosative stress (reactive oxygen species [ROS]; nitric oxide [NO]), neurotrophic factors (brain-derived neurotrophic factor [BDNF]; nerve growth factor [NGF]), and blood-brain barrier (BBB) permeability (S-100β; neuron-specific enolase). ROS concentration significantly increased IAE and following HI (4.9 ± 1.7 mM) compared with that after LI (2.8 ± 1.4 mM) exercise (p < .05). At 60MAE, ROS concentration was higher following HI (2.5 ± 1.2 mM) than after LI (1.5 ± 0.5 mM) and MI (1.4 ± 0.3 mM) conditions (p < .05). Plasma NO IAE increased significantly after MI and HI exercise (p < .05). Serum BDNF, NGF, and S-100b levels were significantly higher IAE following MI and HI exercise (p < .05). BDNF and S-100b were higher IAE following MI (29.6 ± 3.4 ng/mL and 87.1 ± 22.8 ng/L, respectively) and HI (31.4 ± 3.8 ng/mL and 100.6 ± 21.2 ng/L, respectively) than following LI (26.5 ± 3.0 ng/mL and 64.8 ± 19.2 ng/L, respectively) exercise (p < .05). 60MAE, S-100b was higher following HI (71.1 ± 14.5 ng/L) than LI (56.2 ± 14.7 ng/L) exercise (p < .05). NSE levels were not significantly different among all intensity conditions and time points (p > .05). Moderate- and/or high-intensity exercise may induce higher oxidative-nitrosative stress than may low-intensity exercise, which can increase peripheral neurotrophic factor levels by increasing BBB permeability.

Optimizing plasmonic nanoantennas via coordinated multiple coupling

NASA Astrophysics Data System (ADS)

Lin, Linhan; Zheng, Yuebing

2015-10-01

Plasmonic nanoantennas, which can efficiently convert light from free space into sub-wavelength scale with the local field enhancement, are fundamental building blocks for nanophotonic systems. Predominant design methods, which exploit a single type of near- or far-field coupling in pairs or arrays of plasmonic nanostructures, have limited the tunability of spectral response and the local field enhancement. To overcome this limit, we are developing a general strategy towards exploiting the coordinated effects of multiple coupling. Using Au bowtie nanoantenna arrays with metal-insulator-metal configuration as examples, we numerically demonstrate that coordinated design and implementation of various optical coupling effects leads to both the increased tunability in the spectral response and the significantly enhanced electromagnetic field. Furthermore, we design and analyze a refractive index sensor with an ultra-high figure-of-merit (254), a high signal-to-noise ratio and a wide working range of refractive indices, and a narrow-band near-infrared plasmonic absorber with 100% absorption efficiency, high quality factor of up to 114 and a wide range of tunable wavelength from 800 nm to 1,500 nm. The plasmonic nanoantennas that exploit coordinated multiple coupling will benefit a broad range of applications, including label-free bio-chemical detection, reflective filter, optical trapping, hot-electron generation, and heat-assisted magnetic recording.

Multiple scaling power in liquid gallium under pressure conditions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Renfeng; Wang, Luhong; Li, Liangliang

Generally, a single scaling exponent, Df, can characterize the fractal structures of metallic glasses according to the scaling power law. However, when the scaling power law is applied to liquid gallium upon compression, the results show multiple scaling exponents and the values are beyond 3 within the first four coordination spheres in real space, indicating that the power law fails to describe the fractal feature in liquid gallium. The increase in the first coordination number with pressure leads to the fact that first coordination spheres at different pressures are not similar to each other in a geometrical sense. This multiplemore » scaling power behavior is confined within a correlation length of ξ ≈ 14–15 Å at applied pressure according to decay of G(r) in liquid gallium. Beyond this length the liquid gallium system could roughly be viewed as homogeneous, as indicated by the scaling exponent, Ds, which is close to 3 beyond the first four coordination spheres.« less

Safety in the operating theatre--a transition to systems-based care.

PubMed

Weiser, Thomas G; Porter, Michael P; Maier, Ronald V

2013-03-01

All surgeons want the best, safest care for their patients, but providing this requires the complex coordination of multiple disciplines to ensure that all elements of care are timely, appropriate, and well organized. Quality-improvement initiatives are beginning to lead to improvements in the quality of care and coordination amongst teams in the operating room. As the population ages and patients present with more complex disease pathology, the demands for efficient systematization will increase. Although evidence suggests that postoperative mortality rates are declining, there is substantial room for improvement. Multiple quality metrics are used as surrogates for safe care, but surgical teams--including surgeons, anaesthetists, and nurses--must think beyond these simple interventions if they are to effectively communicate and coordinate in the face of increasing demands.

A Novel Rodent Model of Posterior Ischemic Optic Neuropathy

PubMed Central

Wang, Yan; Brown, Dale P.; Duan, Yuanli; Kong, Wei; Watson, Brant D.; Goldberg, Jeffrey L.

2014-01-01

Objectives To develop a reliable, reproducible rat model of posterior ischemic optic neuropathy (PION) and study the cellular responses in the optic nerve and retina. Methods Posterior ischemic optic neuropathy was induced in adult rats by photochemically induced ischemia. Retinal and optic nerve vasculature was examined by fluorescein isothiocyanate–dextran extravasation. Tissue sectioning and immunohistochemistry were used to investigate the pathologic changes. Retinal ganglion cell survival at different times after PION induction, with or without neurotrophic application, was quantified by fluorogold retrograde labeling. Results Optic nerve injury was confirmed after PION induction, including local vascular leakage, optic nerve edema, and cavernous degeneration. Immunostaining data revealed microglial activation and focal loss of astrocytes, with adjacent astrocytic hypertrophy. Up to 23%, 50%, and 70% retinal ganglion cell loss was observed at 1 week, 2 weeks, and 3 weeks, respectively, after injury compared with a sham control group. Experimental treatment by brain-derived neurotrophic factor and ciliary neurotrophic factor remarkably prevented retinal ganglion cell loss in PION rats. At 3 weeks after injury, more than 40% of retinal ganglion cells were saved by the application of neurotrophic factors. Conclusions Rat PION created by photochemically induced ischemia is a reproducible and reliable animal model for mimicking the key features of human PION. Clinical Relevance The correspondence between the features of this rat PION model to those of human PION makes it an ideal model to study the pathophysiologic course of the disease, most of which remains to be elucidated. Furthermore, it provides an optimal model for testing therapeutic approaches for optic neuropathies. PMID:23544206

Metrifonate, like acetylcholine, up-regulates neurotrophic activity of cultured rat astrocytes.

PubMed

Mele, Tina; Jurič, Damijana Mojca

2014-08-01

Metrifonate is an inhibitor of acetylcholinesterase (AChE). Several studies confirmed its positive effects on cognitive impairment in Alzheimer's disease but it was due to adverse events withdrawn from clinical trials. Based on the importance of astrocytes in physiological and pathological brain activities we investigated the impact of metrifonate and, for comparison, acetylcholine on intrinsic neurotrophic activity in these cells. Metabolic activity, intracellular adenosine 5'-triphosphate (ATP) levels and lactate dehydrogenase (LDH) release was measured to examine the impact of metrifonate on viability and integrity of cultured rat cortical astrocytes. The influence of metrifonate, acetylcholine and selective cholinergic ligands on nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) synthesis and secretion was determined by specific two-site enzyme immunoassays. Exposure of cultured astrocytes to metrifonate displayed no toxic effects on cell viability. Metrifonate and acetylcholine potently and transiently elevated NGF and BDNF, but not NT-3, protein levels and secretion with different intensity and time frame of their maximal response. Stimulatory effect on NGF was mimicked by selective nicotinic receptor agonist nicotine and completely blocked by nicotinic antagonist mecamylamine. The impact on BDNF synthesis was mimicked by muscarinic receptor agonist pilocarpine and abolished by selective muscarinic antagonist scopolamine. Metrifonate up-regulates astrocytic NGF and BDNF synthesis in the same manner as acetylcholine, their effect depends on different cholinergic pathways. These results suggest a trophic role of metrifonate, based on a well-known neurotrophic activity of NGF and BDNF in vivo. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Local delivery of glial cell line-derived neurotrophic factor improves facial nerve regeneration after late repair.

PubMed

Barras, Florian M; Kuntzer, Thierry; Zurn, Anne D; Pasche, Philippe

2009-05-01

Facial nerve regeneration is limited in some clinical situations: in long grafts, by aged patients, and when the delay between nerve lesion and repair is prolonged. This deficient regeneration is due to the limited number of regenerating nerve fibers, their immaturity and the unresponsiveness of Schwann cells after a long period of denervation. This study proposes to apply glial cell line-derived neurotrophic factor (GDNF) on facial nerve grafts via nerve guidance channels to improve the regeneration. Two situations were evaluated: immediate and delayed grafts (repair 7 months after the lesion). Each group contained three subgroups: a) graft without channel, b) graft with a channel without neurotrophic factor; and c) graft with a GDNF-releasing channel. A functional analysis was performed with clinical observation of facial nerve function, and nerve conduction study at 6 weeks. Histological analysis was performed with the count of number of myelinated fibers within the graft, and distally to the graft. Central evaluation was assessed with Fluoro-Ruby retrograde labeling and Nissl staining. This study showed that GDNF allowed an increase in the number and the maturation of nerve fibers, as well as the number of retrogradely labeled neurons in delayed anastomoses. On the contrary, after immediate repair, the regenerated nerves in the presence of GDNF showed inferior results compared to the other groups. GDNF is a potent neurotrophic factor to improve facial nerve regeneration in grafts performed several months after the nerve lesion. However, GDNF should not be used for immediate repair, as it possibly inhibits the nerve regeneration.

Serum brain-derived neurotrophic factor, glial-derived neurotrophic factor, nerve growth factor, and neurotrophin-3 levels in children with attention-deficit/hyperactivity disorder.

PubMed

Bilgiç, Ayhan; Toker, Aysun; Işık, Ümit; Kılınç, İbrahim

2017-03-01

It has been suggested that neurotrophins are involved in the etiopathogenesis of attention-deficit/hyperactivity disorder (ADHD). This study aimed to investigate whether there are differences in serum brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and neurotrophin-3 (NTF3) levels between children with ADHD and healthy controls. A total of 110 treatment-naive children with the combined presentation of ADHD and 44 healthy controls aged 8-18 years were enrolled in this study. The severity of ADHD symptoms was determined by scores on the Conners' Parent Rating Scale-Revised Short and Conners' Teacher Rating Scale-Revised Short. The severity of depression and anxiety symptoms of the children were evaluated by the self-report inventories. Serum levels of neurotrophins were measured using commercial enzyme-linked immunosorbent assay kits. The multivariate analysis of covariance (MANCOVA) revealed a significant main effect of groups in the levels of serum neurotrophins, an effect that was independent of age, sex, and the severity of the depression and anxiety. The analysis of covariance (ANCOVA) indicated that the mean serum GDNF and NTF3 levels of ADHD patients were significantly higher than that of controls. However, serum BDNF and NGF levels did not show any significant differences between groups. No correlations between the levels of serum neurotrophins and the severity of ADHD were observed. These results suggest that elevated serum GDNF and NTF3 levels may be related to ADHD in children.

More inflammation but less brain-derived neurotrophic factor in antisocial personality disorder.

PubMed

Wang, Tzu-Yun; Lee, Sheng-Yu; Hu, Ming-Chuan; Chen, Shiou-Lan; Chang, Yun-Hsuan; Chu, Chun-Hsien; Lin, Shih-Hsien; Li, Chia-Ling; Wang, Liang-Jen; Chen, Po See; Chen, Shih-Heng; Huang, San-Yuan; Tzeng, Nian-Sheng; Lee, I Hui; Chen, Kao Chin; Yang, Yen Kuang; Hong, Jau-Shyong; Lu, Ru-Band

2017-11-01

Antisocial personality disorder (ASPD) is highly comorbid with substance use disorders (SUDs). We hypothesize that chronic neuroinflammation and the loss of neurotrophic factors prompts the pathogenesis of both disorders. We used ELISA to measure plasma levels of proinflammatory (tumor necrosis factor-α [TNF-α], C-reactive protein [CRP]) and anti-inflammatory factors (transforming growth factor-β1 [TGF-β1] and interleukin-10 [IL-10]), and brain-derived neurotrophic factor (BDNF) in male patients with ASPD (n=74), SUDs (n=168), ASPD comorbid with SUDs (ASPD+SUDs) (n=438), and Healthy Controls (HCs) (n=81). A multivariate analysis of covariance (MANCOVA) controlled for possible confounders was used to compare cytokines and BDNF levels between groups. The results of MANCOVA adjusted for age showed a significant (p<0.001) main effect of diagnosis on inflammatory factors and BDNF expression in these groups. ASPD, SUDs, and ASPD+SUDs patients had significantly (p<0.001) higher TNF-α levels but lower TGF-β1 and BDNF levels. SUDs and ASPD+SUDs patients had higher IL-10 levels than did ASPD patients and HCs. There was no difference in IL-10 levels between HCs and ASPD. Moreover, subgrouping SUDs and ASPD±SUDs into opioid use disorder (OUD) and other SUDs groups showed that the IL-10 levels were specifically higher in OUD and ASPD±OUD groups than other SUDs (P≤0.001). We conclude that uncontrolled inflammation and losing neurotrophic factors, with or without comorbid SUDs, underlies ASPD. IL-10 expression might be more specifically associated with OUD. Copyright © 2017 Elsevier Ltd. All rights reserved.

Genetics Home Reference: multiple system atrophy

MedlinePlus

... inability to hold the body upright and balanced (postural instability). The other type of multiple system atrophy , ... cells in parts of the nervous system that control movement, balance and coordination, and autonomic functioning. The ...

TGFβ induces GDNF responsiveness in neurons by recruitment of GFRα1 to the plasma membrane

PubMed Central

Peterziel, H.; Unsicker, K.; Krieglstein, K.

2002-01-01

We have previously shown that the neurotrophic effect of glial cell line–derived neurotrophic factor (GDNF) in vitro and in vivo requires the presence of transforming growth factor (TGF)β. Using primary neurons (chick E8 ciliary) we show that the combination of GDNF plus TGFβ promotes survival, whereas the single factors do not. This cooperative effect is inhibited by blocking the extracellular signal-regulated kinase (ERK)/MAPK pathway, but not by interfering with the PI3 kinase signaling cascade. Although there is no functional GDNF signaling in the absence of TGFβ, pretreatment with TGFβ confers GDNF responsiveness to the cells. This is not due to upregulation of GDNF receptors mRNA and protein, but to TGFβ-induced recruitment of the glycosyl-phosphatidylinositol-anchored GDNF receptor (GFR)α1 to the plasma membrane. This is supported by the fact that GDNF in the presence of a soluble GFRα1 can promote survival in the absence of TGFβ. Our data suggest that TGFβ is involved in GFRα1 membrane translocation, thereby permitting GDNF signaling and neurotrophic effects. PMID:12370242

Involvement of Brain-Derived Neurotrophic Factor in Late-Life Depression

PubMed Central

Dwivedi, Yogesh

2013-01-01

Brain-derived neurotrophic factor (BDNF), one of the major neurotrophic factors, plays an important role in the maintenance and survival of neurons, synaptic integrity, and synaptic plasticity. Evidence suggests that BDNF is involved in major depression, such that the level of BDNF is decreased in depressed patients and that antidepressants reverse this decrease. Stress, a major factor in depression, also modulates BDNF expression. These studies have led to the proposal of the neurotrophin hypothesis of depression. Late-life depression is associated with disturbances in structural and neural plasticity as well as impairments in cognitive behavior. Stress and aging also play a crucial role in late-life depression. Many recent studies have suggested that not only expression of BDNF is decreased in the serum/plasma of patients with late-life depression, but structural abnormalities in the brain of these patients may be associated with a polymorphism in the BDNF gene, and that there is a relationship between a BDNF polymorphism and antidepressant remission rates. This review provides a critical review of the involvement of BDNF in major depression, in general, and in late-life depression, in particular. PMID:23570887

Apigenin reverses depression-like behavior induced by chronic corticosterone treatment in mice.

PubMed

Weng, Lianjin; Guo, Xiaohua; Li, Yang; Yang, Xin; Han, Yuanyuan

2016-03-05

Previous researches found that apigenin exerted antidepressant-like effects in rodents. However, it is unclear whether the neurotrophic system is involved in the antidepressant-like effects of apigenin. Our present study aimed to explore the neurotrophic related mechanism of apigenin in depressive-like mice induced by chronic corticosterone treatment. Mice were repeatedly injected with corticosterone (40 mg/kg) subcutaneously (s.c) once daily for consecutive 21 days. Apigenin (20 and 40 mg/kg) and fluoxetine (20 mg/kg) were administered 30 min prior to the corticosterone injection. The behavioral tests indicated that apigenin reversed the reduction of sucrose preference and the elevation of immobility time in mice induced by chronic corticosterone treatment. In addition, the increase in serum corticosterone levels and the decrease in hippocampal brain-derived neurotrophic factor (BDNF) levels in corticosterone-treated mice were also ameliorated by apigenin administration. Taken together, our findings intensively confirmed the antidepressant-like effects of apigenin and indicated that the antidepressant-like mechanism of apigenin was mediated, at least partly by up-regulation of BDNF levels in the hippocampus. Copyright © 2016 Elsevier B.V. All rights reserved.

Absence of Ret Signaling in Mice Causes Progressive and Late Degeneration of the Nigrostriatal System

PubMed Central

Kramer, Edgar R; Aron, Liviu; Ramakers, Geert M. J; Seitz, Sabine; Zhuang, Xiaoxi; Beyer, Klaus; Smidt, Marten P; Klein, Rüdiger

2007-01-01

Support of ageing neurons by endogenous neurotrophic factors such as glial cell line–derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) may determine whether the neurons resist or succumb to neurodegeneration. GDNF has been tested in clinical trials for the treatment of Parkinson disease (PD), a common neurodegenerative disorder characterized by the loss of midbrain dopaminergic (DA) neurons. BDNF modulates nigrostriatal functions and rescues DA neurons in PD animal models. The physiological roles of GDNF and BDNF signaling in the adult nigrostriatal DA system are unknown. We generated mice with regionally selective ablations of the genes encoding the receptors for GDNF (Ret) and BDNF (TrkB). We find that Ret, but not TrkB, ablation causes progressive and adult-onset loss of DA neurons specifically in the substantia nigra pars compacta, degeneration of DA nerve terminals in striatum, and pronounced glial activation. These findings establish Ret as a critical regulator of long-term maintenance of the nigrostriatal DA system and suggest conditional Ret mutants as useful tools for gaining insights into the molecular mechanisms involved in the development of PD. PMID:17298183

The Transition of Acute Postoperative Pain to Chronic Pain: An Integrative Overview of Research on Mechanisms.

PubMed

Chapman, C Richard; Vierck, Charles J

2017-04-01

The nature of the transition from acute to chronic pain still eludes explanation, but chronic pain resulting from surgery provides a natural experiment that invites clinical epidemiological investigation and basic scientific inquiry into the mechanisms of this transition. The primary purpose of this article is to review current knowledge and hypotheses on the transition from acute to persistent postsurgical pain, summarizing literature on clinical epidemiological studies of persistent postsurgical pain development, as well as basic neurophysiological studies targeting mechanisms in the periphery, spinal cord, and brain. The second purpose of this article is to integrate theory, information, and causal reasoning in these areas. Conceptual mapping reveals 5 classes of hypotheses pertaining to pain. These propose that chronic pain results from: 1) persistent noxious signaling in the periphery; 2) enduring maladaptive neuroplastic changes at the spinal dorsal horn and/or higher central nervous system structures reflecting a multiplicity of factors, including peripherally released neurotrophic factors and interactions between neurons and microglia; 3) compromised inhibitory modulation of noxious signaling in medullary-spinal pathways; 4) descending facilitatory modulation; and 5) maladaptive brain remodeling in function, structure, and connectivity. The third purpose of this article is to identify barriers to progress and review opportunities for advancing the field. This review reveals a need for a concerted, strategic effort toward integrating clinical epidemiology, basic science research, and current theory about pain mechanisms to hasten progress toward understanding, managing, and preventing persistent postsurgical pain. The development of chronic pain after surgery is a major clinical problem that provides an opportunity to study the transition from acute to chronic pain at epidemiologic and basic science levels. Strategic, coordinated, multidisciplinary research efforts targeting mechanisms of pain chronification can to help minimize or eliminate persistent postsurgical pain. Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.

Pediatric Care Coordination: Lessons Learned and Future Priorities.

PubMed

Cady, Rhonda G; Looman, Wendy S; Lindeke, Linda L; LaPlante, Bonnie; Lundeen, Barbara; Seeley, Amanda; Kautto, Mary E

2015-09-30

A fundamental component of the medical home model is care coordination. In Minnesota, this model informed design and implementation of the state's health care home (HCH) model, a key element of statewide healthcare reform legislation. Children with medical complexity (CMC) often require care from multiple specialists and community resources. Coordinating this multi-faceted care within the HCH is challenging. This article describes the need for specialized models of care coordination for CMC. Two models of care coordination for CMC were developed to address this challenge. The TeleFamilies Model of Pediatric Care Coordination uses an advanced practice registered nurse care (APRN) coordinator embedded within an established HCH. The PRoSPer Model of Pediatric Care Coordination uses a registered nurse/social worker care coordinator team embedded within a specialty care system. We describe key findings from implementation of these models, and conclude with lessons learned. Replication of the models is encouraged to increase the evidence base for care coordination for the growing population of children with medical complexities.

Block coordination copolymers

DOEpatents

Koh, Kyoung Moo; Wong-Foy, Antek G; Matzger, Adam J; Benin, Annabelle I; Willis, Richard R

2014-11-11

The present invention provides compositions of crystalline coordination copolymers wherein multiple organic molecules are assembled to produce porous framework materials with layered or core-shell structures. These materials are synthesized by sequential growth techniques such as the seed growth technique. In addition, the invention provides a simple procedure for controlling functionality.

Block coordination copolymers

DOEpatents

Koh, Kyoung Moo; Wong-Foy, Antek G.; Matzger, Adam J.; Benin, Annabelle I.; Willis, Richard R.

2012-12-04

The present invention provides compositions of crystalline coordination copolymers wherein multiple organic molecules are assembled to produce porous framework materials with layered or core-shell structures. These materials are synthesized by sequential growth techniques such as the seed growth technique. In addition, the invention provides a simple procedure for controlling functionality.

Block coordination copolymers

DOEpatents

Koh, Kyoung Moo; Wong-Foy, Antek G; Matzger, Adam J; Benin, Annabelle I; Willis, Richard R

2012-11-13

The present invention provides compositions of crystalline coordination copolymers wherein multiple organic molecules are assembled to produce porous framework materials with layered or core-shell structures. These materials are synthesized by sequential growth techniques such as the seed growth technique. In addition, the invention provides a simple procedure for controlling functionality.

Bimanual motor coordination controlled by cooperative interactions in intrinsic and extrinsic coordinates.

PubMed

Sakurada, Takeshi; Ito, Koji; Gomi, Hiroaki

2016-01-01

Although strong motor coordination in intrinsic muscle coordinates has frequently been reported for bimanual movements, coordination in extrinsic visual coordinates is also crucial in various bimanual tasks. To explore the bimanual coordination mechanisms in terms of the frame of reference, here we characterized implicit bilateral interactions in visuomotor tasks. Visual perturbations (finger-cursor gain change) were applied while participants performed a rhythmic tracking task with both index fingers under an in-phase or anti-phase relationship in extrinsic coordinates. When they corrected the right finger's amplitude, the left finger's amplitude unintentionally also changed [motor interference (MI)], despite the instruction to keep its amplitude constant. Notably, we observed two specificities: one was large MI and low relative-phase variability (PV) under the intrinsic in-phase condition, and the other was large MI and high PV under the extrinsic in-phase condition. Additionally, using a multiple-interaction model, we successfully decomposed MI into intrinsic components caused by motor correction and extrinsic components caused by visual-cursor mismatch of the right finger's movements. This analysis revealed that the central nervous system facilitates MI by combining intrinsic and extrinsic components in the condition with in-phases in both intrinsic and extrinsic coordinates, and that under-additivity of the effects is explained by the brain's preference for the intrinsic interaction over extrinsic interaction. In contrast, the PV was significantly correlated with the intrinsic component, suggesting that the intrinsic interaction dominantly contributed to bimanual movement stabilization. The inconsistent features of MI and PV suggest that the central nervous system regulates multiple levels of bilateral interactions for various bimanual tasks. © 2015 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

History of Glial Cell Line-Derived Neurotrophic Factor (GDNF) and Its Use for Spinal Cord Injury Repair.

PubMed

Walker, Melissa J; Xu, Xiao-Ming

2018-06-13

Following an initial mechanical insult, traumatic spinal cord injury (SCI) induces a secondary wave of injury, resulting in a toxic lesion environment inhibitory to axonal regeneration. This review focuses on the glial cell line-derived neurotrophic factor (GDNF) and its application, in combination with other factors and cell transplantations, for repairing the injured spinal cord. As studies of recent decades strongly suggest that combinational treatment approaches hold the greatest therapeutic potential for the central nervous system (CNS) trauma, future directions of combinational therapies will also be discussed.

Pleiotropy of tissue-specific growth factors: from neurons to vessels via the bone marrow

PubMed Central

Duda, Dan G.; Jain, Rakesh K.

2005-01-01

Recent evidence has demonstrated that endothelial-specific growth factors affect the development of apparently unrelated organs and cells. Expanding this evidence further, new findings in this issue of the JCI show that neurotrophic factors can affect neovascularization. Neurotrophic factors achieve proangiogenic effects not only by directly affecting endothelial cells, but also by recruiting hematopoietic precursors. Further understanding of the biology of angiogenic factors, as well as of the function of hematopoietic cells in tissue neovascularization, will lead to improved therapeutic strategies for the treatment of diseases ranging from ischemia to cancer. PMID:15765145

Coordination of receptor signaling in multiple hematopoietic cell lineages by the adaptor protein SLP-76.

PubMed

Jordan, Martha S; Koretzky, Gary A

2010-04-01

The adaptor protein SLP-76 is expressed in multiple hematopoietic lineages including T cells, platelets, and neutrophils. SLP-76 mediated signaling is dependent on its multiple protein interaction domains, as it creates a scaffold on which key signaling complexes are built. SLP-76 is critical for supporting signaling downstream of both immunoreceptors and integrins. The signaling molecules used both upstream and downstream of SLP-76 are similar among these receptors and across cell types; however, important differences exist. Appreciating how SLP-76 coordinates signal transduction across different cell and receptor types provides insights into the complex interplay of pathways critical for activation of cells of the immune system that are essential for host defense.

Analyzing Group Coordination when Solving Geometry Problems with Dynamic Geometry Software

ERIC Educational Resources Information Center

Oner, Diler

2013-01-01

In CSCL research, collaborative activity is conceptualized along various yet intertwined dimensions. When functioning within these multiple dimensions, participants make use of several resources, which can be social or content-related (and sometimes temporal) in nature. It is the effective coordination of these resources that appears to…

Multiple Sensory-Motor Pathways Lead to Coordinated Visual Attention

ERIC Educational Resources Information Center

Yu, Chen; Smith, Linda B.

2017-01-01

Joint attention has been extensively studied in the developmental literature because of overwhelming evidence that the ability to socially coordinate visual attention to an object is essential to healthy developmental outcomes, including language learning. The goal of this study was to understand the complex system of sensory-motor behaviors that…

Market-Based Coordination and Auditing Mechanisms for Self-Interested Multi-Robot Systems

ERIC Educational Resources Information Center

Ham, MyungJoo

2009-01-01

We propose market-based coordinated task allocation mechanisms, which allocate complex tasks that require synchronized and collaborated services of multiple robot agents to robot agents, and an auditing mechanism, which ensures proper behaviors of robot agents by verifying inter-agent activities, for self-interested, fully-distributed, and…

Curcumin attenuates surgery-induced cognitive dysfunction in aged mice.

PubMed

Wu, Xiang; Chen, Huixin; Huang, Chunhui; Gu, Xinmei; Wang, Jialing; Xu, Dilin; Yu, Xin; Shuai, Chu; Chen, Liping; Li, Shun; Xu, Yiguo; Gao, Tao; Ye, Mingrui; Su, Wei; Liu, Haixiong; Zhang, Jinrong; Wang, Chuang; Chen, Junping; Wang, Qinwen; Cui, Wei

2017-06-01

Post-operative cognitive dysfunction (POCD) is associated with elderly patients undergoing surgery. However, pharmacological treatments for POCD are limited. In this study, we found that curcumin, an active compound derived from Curcuma longa, ameliorated the cognitive dysfunction following abdominal surgery in aged mice. Further, curcumin prevented surgery-induced anti-oxidant enzyme activity. Curcumin also increased brain-derived neurotrophic factor (BDNF)-positive area and expression of pAkt in the brain, suggesting that curcumin activated BDNF signaling in aged mice. Furthermore, curcumin neutralized cholinergic dysfunction involving choline acetyltransferase expression induced by surgery. These results strongly suggested that curcumin prevented cognitive impairments via multiple targets, possibly by increasing the activity of anti-oxidant enzymes, activation of BDNF signaling, and neutralization of cholinergic dysfunction, concurrently. Based on these novel findings, curcumin might be a potential agent in POCD prophylaxis and treatment.

[To cognize retinitis pigmentosa with scientific view].

PubMed

Li, Gen-lin

2009-03-01

Retinitis pigmentosa (RP) is the most common inherited eye disease that usually leads into blind, and is high simplex and clinical heterogeneity. Recent years, some new hereditary forms have been found, such as digenic RP, mitochondrial RP, incomplete dominant inheritance RP. The phenotype of RP is multiplicity. Incompatible phenomenon between genotype and phenotypes was shown in some genes such as peripherin/RDS, RHO, RP2 and RP3. The complicated phenotype was shown in the rare RP forms, such as centricity RP, stemma RP, retinitis pigmentosa sine pigmento, and retinal degeneration slow. Retinal transplantation, retinal implantation, drug and neurotrophic factor therapy, and gene therapy have been well studied worldwide and presented some hopeful efficacy. Ophthalmologists and practitioners should cognize the new advance and new knowledge on RP therapy with a scientific view for better serving the RP patients.

Genotet: An Interactive Web-based Visual Exploration Framework to Support Validation of Gene Regulatory Networks.

PubMed

Yu, Bowen; Doraiswamy, Harish; Chen, Xi; Miraldi, Emily; Arrieta-Ortiz, Mario Luis; Hafemeister, Christoph; Madar, Aviv; Bonneau, Richard; Silva, Cláudio T

2014-12-01

Elucidation of transcriptional regulatory networks (TRNs) is a fundamental goal in biology, and one of the most important components of TRNs are transcription factors (TFs), proteins that specifically bind to gene promoter and enhancer regions to alter target gene expression patterns. Advances in genomic technologies as well as advances in computational biology have led to multiple large regulatory network models (directed networks) each with a large corpus of supporting data and gene-annotation. There are multiple possible biological motivations for exploring large regulatory network models, including: validating TF-target gene relationships, figuring out co-regulation patterns, and exploring the coordination of cell processes in response to changes in cell state or environment. Here we focus on queries aimed at validating regulatory network models, and on coordinating visualization of primary data and directed weighted gene regulatory networks. The large size of both the network models and the primary data can make such coordinated queries cumbersome with existing tools and, in particular, inhibits the sharing of results between collaborators. In this work, we develop and demonstrate a web-based framework for coordinating visualization and exploration of expression data (RNA-seq, microarray), network models and gene-binding data (ChIP-seq). Using specialized data structures and multiple coordinated views, we design an efficient querying model to support interactive analysis of the data. Finally, we show the effectiveness of our framework through case studies for the mouse immune system (a dataset focused on a subset of key cellular functions) and a model bacteria (a small genome with high data-completeness).

Force-independent distribution of correlated neural inputs to hand muscles during three-digit grasping.

PubMed

Poston, Brach; Danna-Dos Santos, Alessander; Jesunathadas, Mark; Hamm, Thomas M; Santello, Marco

2010-08-01

The ability to modulate digit forces during grasping relies on the coordination of multiple hand muscles. Because many muscles innervate each digit, the CNS can potentially choose from a large number of muscle coordination patterns to generate a given digit force. Studies of single-digit force production tasks have revealed that the electromyographic (EMG) activity scales uniformly across all muscles as a function of digit force. However, the extent to which this finding applies to the coordination of forces across multiple digits is unknown. We addressed this question by asking subjects (n = 8) to exert isometric forces using a three-digit grip (thumb, index, and middle fingers) that allowed for the quantification of hand muscle coordination within and across digits as a function of grasp force (5, 20, 40, 60, and 80% maximal voluntary force). We recorded EMG from 12 muscles (6 extrinsic and 6 intrinsic) of the three digits. Hand muscle coordination patterns were quantified in the amplitude and frequency domains (EMG-EMG coherence). EMG amplitude scaled uniformly across all hand muscles as a function of grasp force (muscle x force interaction: P = 0.997; cosines of angle between muscle activation pattern vector pairs: 0.897-0.997). Similarly, EMG-EMG coherence was not significantly affected by force (P = 0.324). However, coherence was stronger across extrinsic than that across intrinsic muscle pairs (P = 0.0039). These findings indicate that the distribution of neural drive to multiple hand muscles is force independent and may reflect the anatomical properties or functional roles of hand muscle groups.

Target-based calibration method for multifields of view measurement using multiple stereo digital image correlation systems

NASA Astrophysics Data System (ADS)

Dong, Shuai; Yu, Shanshan; Huang, Zheng; Song, Shoutan; Shao, Xinxing; Kang, Xin; He, Xiaoyuan

2017-12-01

Multiple digital image correlation (DIC) systems can enlarge the measurement field without losing effective resolution in the area of interest (AOI). However, the results calculated in substereo DIC systems are located in its local coordinate system in most cases. To stitch the data obtained by each individual system, a data merging algorithm is presented in this paper for global measurement of multiple stereo DIC systems. A set of encoded targets is employed to assist the extrinsic calibration, of which the three-dimensional (3-D) coordinates are reconstructed via digital close range photogrammetry. Combining the 3-D targets with precalibrated intrinsic parameters of all cameras, the extrinsic calibration is significantly simplified. After calculating in substereo DIC systems, all data can be merged into a universal coordinate system based on the extrinsic calibration. Four stereo DIC systems are applied to a four point bending experiment of a steel reinforced concrete beam structure. Results demonstrate high accuracy for the displacement data merging in the overlapping field of views (FOVs) and show feasibility for the distributed FOVs measurement.

Lessons Learned from Coordinating Relay Activities at Mars

NASA Technical Reports Server (NTRS)

Gladden, Roy E.; Hwang, Pauline; Waggoner, Bruce; McLaughlin, Bruce; Fieseler, Paul; Thomas, Reid; Bigwood, Maria; Herrera, Paul

2005-01-01

The Mission Management Office at the Jet Propulsion Laboratory was tasked with coordinating the relay of data between multiple spacecraft at Mars in support of the Mars Exploration Rover Missions in early 2004. The confluence of three orbiters (Mars Global Surveyor, Mars Odyssey, and Mars Express), two rovers (Spirit and Opportunity), and one lander (Beagle 2) has provided a challenging operational scenario that required careful coordination between missions to provide the necessary support and to avoid potential interference during simultaneous relay sessions. As these coordination efforts progressed, several important lessons were learned that should be applied to future Mars relay activities.

Age-Related Differences in Multiple Task Monitoring

PubMed Central

Todorov, Ivo; Del Missier, Fabio; Mäntylä, Timo

2014-01-01

Coordinating multiple tasks with narrow deadlines is particularly challenging for older adults because of age related decline in cognitive control functions. We tested the hypothesis that multiple task performance reflects age- and gender-related differences in executive functioning and spatial ability. Young and older adults completed a multitasking session with four monitoring tasks as well as separate tasks measuring executive functioning and spatial ability. For both age groups, men exceeded women in multitasking, measured as monitoring accuracy. Individual differences in executive functioning and spatial ability were independent predictors of young adults' monitoring accuracy, but only spatial ability was related to sex differences. For older adults, age and executive functioning, but not spatial ability, predicted multitasking performance. These results suggest that executive functions contribute to multiple task performance across the adult life span and that reliance on spatial skills for coordinating deadlines is modulated by age. PMID:25215609

Price competition and equilibrium analysis in multiple hybrid channel supply chain

NASA Astrophysics Data System (ADS)

Kuang, Guihua; Wang, Aihu; Sha, Jin

2017-06-01

The amazing boom of Internet and logistics industry prompts more and more enterprises to sell commodity through multiple channels. Such market conditions make the participants of multiple hybrid channel supply chain compete each other in traditional and direct channel at the same time. This paper builds a two-echelon supply chain model with a single manufacturer and a single retailer who both can choose different channel or channel combination for their own sales, then, discusses the price competition and calculates the equilibrium price under different sales channel selection combinations. Our analysis shows that no matter the manufacturer and retailer choose same or different channel price to compete, the equilibrium price does not necessarily exist the equilibrium price in the multiple hybrid channel supply chain and wholesale price change is not always able to coordinate supply chain completely. We also present the sufficient and necessary conditions for the existence of equilibrium price and coordination wholesale price.

Age-related differences in multiple task monitoring.

PubMed

Todorov, Ivo; Del Missier, Fabio; Mäntylä, Timo

2014-01-01

Coordinating multiple tasks with narrow deadlines is particularly challenging for older adults because of age related decline in cognitive control functions. We tested the hypothesis that multiple task performance reflects age- and gender-related differences in executive functioning and spatial ability. Young and older adults completed a multitasking session with four monitoring tasks as well as separate tasks measuring executive functioning and spatial ability. For both age groups, men exceeded women in multitasking, measured as monitoring accuracy. Individual differences in executive functioning and spatial ability were independent predictors of young adults' monitoring accuracy, but only spatial ability was related to sex differences. For older adults, age and executive functioning, but not spatial ability, predicted multitasking performance. These results suggest that executive functions contribute to multiple task performance across the adult life span and that reliance on spatial skills for coordinating deadlines is modulated by age.

Time-Coordination Strategies and Control Laws for Multi-Agent Unmanned Systems

NASA Technical Reports Server (NTRS)

Puig-Navarro, Javier; Hovakimyan, Naira; Allen, B. Danette

2017-01-01

Time-critical coordination tools for unmanned systems can be employed to enforce the type of temporal constraints required in terminal control areas, ensure minimum distance requirements among vehicles are satisfied, and successfully perform coordinated missions. In comparison with previous literature, this paper presents an ampler spectrum of coordination and temporal specifications for unmanned systems, and proposes a general control law that can enforce this range of constraints. The constraint classification presented con- siders the nature of the desired arrival window and the permissible coordination errors to define six different types of time-coordination strategies. The resulting decentralized coordination control law allows the vehicles to negotiate their speeds along their paths in response to information exchanged over the communication network. This control law organizes the different members in the fleet hierarchically per their behavior and informational needs as reference agent, leaders, and followers. Examples and simulation results for all the coordination strategies presented demonstrate the applicability and efficacy of the coordination control law for multiple unmanned systems.

A Neuroprotective Sericin Hydrogel As an Effective Neuronal Cell Carrier for the Repair of Ischemic Stroke.

PubMed

Wang, Zheng; Wang, Jian; Jin, Yang; Luo, Zhen; Yang, Wen; Xie, Hongjian; Huang, Kai; Wang, Lin

2015-11-11

Ischemic stroke causes extensive cellular loss that impairs brain functions, resulting in severe disabilities. No effective treatments are currently available for brain tissue regeneration. The need to develop effective therapeutic approaches for treating stroke is compelling. A tissue engineering approach employing a hydrogel carrying both cells and neurotrophic cytokines to damaged regions is an encouraging alternative for neuronal repair. However, this approach is often challenged by low in vivo cell survival rate, and low encapsulation efficiency and loss of cytokines. To address these limitations, we propose to develop a biomaterial that can form a matrix capable of improving in vivo survival of transplanted cells and reducing in vivo loss of cytokines. Here, we report that using sericin, a natural protein from silk, we have fabricated a genipin-cross-linked sericin hydrogel (GSH) with porous structure and mild swelling ratio. The GSH supports the effective attachment and growth of neurons in vitro. Strikingly, our data reveal that sericin protein is intrinsically neurotrophic and neuroprotective, promoting axon extension and branching as well as preventing primary neurons from hypoxia-induced cell death. Notably, these functions are inherited by the GSH's degradation products, which might spare a need of incorporating costly cytokines. We further demonstrate that this neurotrophic effect is dependent on the Lkb1-Nuak1 pathway, while the neuroprotective effect is realized through regulating the Bcl-2/Bax protein ratio. Importantly, when transplanted in vivo, the GSH gives a high cell survival rate and allows the cells to continuously proliferate. Together, this work unmasks the neurotrophic and neuroprotective functions for sericin and provides strong evidence justifying the GSH's suitability as a potential neuronal cell delivery vehicle for ischemic stroke repair.

The Neuroprotective Effects of Flaxseed Oil Supplementation on Functional Motor Recovery in a Model of Ischemic Brain Stroke: Upregulation of BDNF and GDNF.

PubMed

Bagheri, Abolqasem; Talei, Sahand; Hassanzadeh, Negar; Mokhtari, Tahmineh; Akbari, Mohammad; Malek, Fatemeh; Jameie, Seyed Behnamedin; Sadeghi, Yousef; Hassanzadeh, Gholamreza

2017-12-01

Cerebral ischemic stroke is a common leading cause of disability. Flaxseed is a richest plant-based source of antioxidants. In this study, the effects of flaxseed oil (FSO) pretreatment on functional motor recovery and gene expression and protein content of neurotrophic factors in motor cortex area in rat model of brain ischemia/reperfusion (I/R) were assessed. Transient middle cerebral artery occlusion (tMCAo) in rats was used as model brain I/R. Rats (6 in each group) were randomly divided into four groups of Control (Co+normal saline [NS]), Sham (Sh+NS), tMCAo+NS and tMCAo+FSO. After three weeks of pretreatment with vehicle or FSO (0.2 ml~800 mg/kg body weight), the rats were operated in sham and ischemic groups. Ischemia was induced for 1 h and then reperfused. After 24 h of reperfusion, neurological examination was performed, and animals were sacrificed, and their brains were used for molecular and histopathological studies. FSO significantly improved the functional motor recovery compared with tMCAo+NS group (P<0.05). A significant reduction in brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) mRNAs and protein levels were observed in the tMCAo+NS group compared with Co+NS and Sh+NS group (P<0.05). A significant increase of BDNF and GDNF mRNAs and proteins was recorded in the tMCAo+FSO group compared with Co+NS, Sh+NS and tMCAO+NS groups (P<0.05). The results of the current study demonstrated that pretreatment with FSO had neuroprotective effects on motor cortex area following cerebral ischemic stroke by increasing the neurotrophic factors (BDNF, GDNF).

Neurotrophic Effect of Citrus 5-Hydroxy-3,6,7,8,3′,4′-Hexamethoxyflavone: Promotion of Neurite Outgrowth via cAMP/PKA/CREB Pathway in PC12 Cells

PubMed Central

Lai, Hui-Chi; Wu, Ming-Jiuan; Chen, Pei-Yi; Sheu, Ting-Ting; Chiu, Szu-Ping; Lin, Meng-Han; Ho, Chi-Tang; Yen, Jui-Hung

2011-01-01

5-Hydroxy-3,6,7,8,3′,4′-hexamethoxyflavone (5-OH-HxMF), a hydroxylated polymethoxyflavone, is found exclusively in the Citrus genus, particularly in the peels of sweet orange. In this research, we report the first investigation of the neurotrophic effects and mechanism of 5-OH-HxMF in PC12 pheochromocytoma cells. We found that 5-OH-HxMF can effectively induce PC12 neurite outgrowth accompanied with the expression of neuronal differentiation marker protein growth-associated protein-43(GAP-43). 5-OH-HxMF caused the enhancement of cyclic AMP response element binding protein (CREB) phosphorylation, c-fos gene expression and CRE-mediated transcription, which was inhibited by 2-naphthol AS-E phosphate (KG-501), a specific antagonist for the CREB-CBP complex formation. Moreover, 5-OH-HxMF-induced both CRE transcription activity and neurite outgrowth were inhibited by adenylate cyclase and protein kinase A (PKA) inhibitor, but not MEK1/2, protein kinase C (PKC), phosphatidylinositol 3-kinase (PI3K) or calcium/calmodulin-dependent protein kinase (CaMK) inhibitor. Consistently, 5-OH-HxMF treatment increased the intracellular cAMP level and downstream component, PKA activity. We also found that addition of K252a, a TrKA antagonist, significantly inhibited NGF- but not 5-OH-HxMF-induced neurite outgrowth. These results reveal for the first time that 5-OH-HxMF is an effective neurotrophic agent and its effect is mainly through a cAMP/PKA-dependent, but TrKA-independent, signaling pathway coupling with CRE-mediated gene transcription. A PKC-dependent and CREB-independent pathway was also involved in its neurotrophic action. PMID:22140566

Alterations in BDNF (brain derived neurotrophic factor) and GDNF (glial cell line-derived neurotrophic factor) serum levels in bipolar disorder: The role of lithium.

PubMed

Tunca, Zeliha; Ozerdem, Aysegul; Ceylan, Deniz; Yalçın, Yaprak; Can, Güneş; Resmi, Halil; Akan, Pınar; Ergör, Gül; Aydemir, Omer; Cengisiz, Cengiz; Kerim, Doyuran

2014-09-01

Brain-derived neurotrophic factor (BDNF) has been consistently reported to be decreased in mania or depression in bipolar disorders. Evidence suggests that Glial cell line-derived neurotrophic factor (GDNF) has a role in the pathogenesis of mood disorders. Whether GDNF and BDNF act in the same way across different episodes in bipolar disorders is unclear. BDNF and GDNF serum levels were measured simultaneously by enzyme-linked immunosorbent assay (ELISA) method in 96 patients diagnosed with bipolar disorder according to DSM-IV (37 euthymic, 33 manic, 26 depressed) in comparison to 61 healthy volunteers. SCID- I and SCID-non patient version were used for clinical evaluation of the patients and healthy volunteers respectively. Correlations between the two trophic factor levels, and medication dose, duration and serum levels of lithium or valproate were studied across different episodes of illness. Patients had significantly lower BDNF levels during mania and depression compared to euthymic patients and healthy controls. GDNF levels were not distinctive. However GDNF/BDNF ratio was higher in manic state compared to euthymia and healthy controls. Significant negative correlation was observed between BDNF and GDNF levels in euthymic patients. While BDNF levels correlated positively, GDNF levels correlated negatively with lithium levels. Regression analysis confirmed that lithium levels predicted only GDNF levels positively in mania, and negatively in euthymia. Small sample size in different episodes and drug-free patients was the limitation of thestudy. Current data suggests that lithium exerts its therapeutic action by an inverse effect on BDNF and GDNF levels, possibly by up-regulating BDNF and down-regulating GDNF to achieve euthymia. Copyright © 2014 Elsevier B.V. All rights reserved.

Physical exercise in overweight to obese individuals induces metabolic- and neurotrophic-related structural brain plasticity

PubMed Central

Mueller, Karsten; Möller, Harald E.; Horstmann, Annette; Busse, Franziska; Lepsien, Jöran; Blüher, Matthias; Stumvoll, Michael; Villringer, Arno; Pleger, Burkhard

2015-01-01

Previous cross-sectional studies on body-weight-related alterations in brain structure revealed profound changes in the gray matter (GM) and white matter (WM) that resemble findings obtained from individuals with advancing age. This suggests that obesity may lead to structural brain changes that are comparable with brain aging. Here, we asked whether weight-loss-dependent improved metabolic and neurotrophic functioning parallels the reversal of obesity-related alterations in brain structure. To this end we applied magnetic resonance imaging (MRI) together with voxel-based morphometry and diffusion-tensor imaging in overweight to obese individuals who participated in a fitness course with intensive physical training twice a week over a period of 3 months. After the fitness course, participants presented, with inter-individual heterogeneity, a reduced body mass index (BMI), reduced serum leptin concentrations, elevated high-density lipoprotein-cholesterol (HDL-C), and alterations of serum brain-derived neurotrophic factor (BDNF) concentrations suggesting changes of metabolic and neurotrophic function. Exercise-dependent changes in BMI and serum concentration of BDNF, leptin, and HDL-C were related to an increase in GM density in the left hippocampus, the insular cortex, and the left cerebellar lobule. We also observed exercise-dependent changes of diffusivity parameters in surrounding WM structures as well as in the corpus callosum. These findings suggest that weight-loss due to physical exercise in overweight to obese participants induces profound structural brain plasticity, not primarily of sensorimotor brain regions involved in physical exercise, but of regions previously reported to be structurally affected by an increased body weight and functionally implemented in gustation and cognitive processing. PMID:26190989

Total flavonoid extract from Dracoephalum moldavica L. attenuates β-amyloid-induced toxicity through anti-amyloidogenesic and neurotrophic pathways.

PubMed

Liu, Qing-Shan; Jiang, Hai-Lun; Wang, Yu; Wang, Lin-Lin; Zhang, Jun-Xia; He, Cheng-Hui; Shao, Shuai; Zhang, Tian-Tai; Xing, Jian-Guo; Liu, Rui

2018-01-15

Alzheimer's disease (AD) is an incurable neurodegenerative disorder characterized by global cognitive impairment that involves accumulation of amyloid-beta peptides (Aβ) in the brain. Herbal approaches can be used as alternative medicines to slow the progression of AD. This study aimed to determine the beneficial effects and potential underlying mechanisms of total flavonoid extract from Dracoephalum moldavica L. (TFDM) for attenuating Alzheimer-related deficits induced by Aβ. We used amyloid precursor protein (APP) and presenilin 1 (PS1) double transgenic mice and copper-injured APP Swedish mutation overexpressing SH-SY5Y cells to evaluate the beneficial effects of TFDM. Further, identifying the mechanisms of action was conducted on anti-amyloidogenic and neurotrophic transductions. Our results indicated that TFDM treatment ameliorated cognitive impairments and neurodegeneration and improved the antioxidant defense system in APP/PS1 mice. TFDM also reduced Aβ burden by relieving Aβ deposition, decreasing insoluble Aβ levels, and inhibiting β-amyloidogenic processing pathway involving downregulation of β-secretase and β-C-terminal fragment in the brain. In the in vitro model of AD, TFDM treatment protected injured cells, and combined with the beneficial effects of decreasing APP levels, lowered Aβ 1-42 and regulated the redox imbalance. Moreover, TFDM preserved the extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor pathway both in vitro and in vivo. In conclusion, TFDM clearly demonstrated neuroprotective effects by restoring the anti-amyloidogenic and neurotrophic transductions in the context of AD-associated deficits. These findings indicate the potential use of herb-based substances as supplements or potential alternative supplements for attenuating the progression of AD. Copyright © 2017. Published by Elsevier Inc.

Cranial electrotherapy stimulation affects mood state but not levels of peripheral neurotrophic factors or hypothalamic- pituitary-adrenal axis regulation.

PubMed

Roh, Hee-Tae; So, Wi-Young

2017-01-01

Cranial electrotherapy stimulation (CES) is reported to aid in relieving symptoms of depression and anxiety, though the mechanism underlying this effect remains unclear. Therefore, the present study aimed to evaluate changes in the hypothalamic-pituitary-adrenal (HPA) axis response and levels of neurotrophic factors, as well as changes in mood state, in patients undergoing CES therapy. Fifty healthy postmenopausal women were randomly assigned to either a Sham CES group (n = 25) or an Active CES group (n = 25). CES treatment was conducted in 20-minute sessions, three times per week for 8 weeks, using a micro current cranial electrotherapy stimulator. Blood samples were collected prior to and following the 8-week treatment period for measurement of cortisol, adrenocorticotropic hormone (ACTH), brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF) levels. Changes in mood state were also examined at the time of blood collection using the Profile of Mood States (POMS). No significant differences in cortisol, ACTH, BDNF, or NGF were observed between the two participant groups (p > 0.05) following the treatment period. However, those in the Active CES group exhibited significantly decreased Tension-Anxiety and Depression-Dejection scores on the POMS relative to pre-treatment scores (p < 0.05). Furthermore, Depression-Dejection scores following treatment were significantly lower in the Active CES group than in the Sham CES group (p < 0.05). No significant differences were observed in any other POMS scores such as Anger-Hostility, Vigor-Activity, Fatigue-Inertia, and Confusion-Bewilderment (p > 0.05). These results suggest that 8 weeks of CES treatment does not induce changes in blood levels of neurotrophic factors or HPA-axis-related hormones, though such treatment may be effective in treating symptoms of anxiety and depression.

Rapid transient isoform-specific neuregulin1 transcription in motor neurons is regulated by neurotrophic factors and axon-target interactions.

PubMed

Wang, Jiajing; Hmadcha, Abdelkrim; Zakarian, Vaagn; Song, Fei; Loeb, Jeffrey A

2015-09-01

The neuregulins (NRGs) are a family of alternatively spliced factors that play important roles in nervous system development and disease. In motor neurons, NRG1 expression is regulated by activity and neurotrophic factors, however, little is known about what controls isoform-specific transcription. Here we show that NRG1 expression in the chick embryo increases in motor neurons that have extended their axons and that limb bud ablation before motor axon outgrowth prevents this induction, suggesting a trophic role from the developing limb. Consistently, NRG1 induction after limb bud ablation can be rescued by adding back the neurotrophic factors BDNF and GDNF. Mechanistically, BDNF induces a rapid and transient increase in type I and type III NRG1 mRNAs that peak at 4h in rat embryonic ventral spinal cord cultures. Blocking MAPK or PI3K signaling or blocking transcription with Actinomycin D blocks BDNF induced NRG1 gene induction. BDNF had no effect on mRNA degradation, suggesting that transcriptional activation rather than message stability is important. Furthermore, BDNF activates a reporter construct that includes 700bp upstream of the type I NRG1 start site. Protein synthesis is also required for type I NRG1 mRNA transcription as cycloheximide produced a super-induction of type I, but not type III NRG1 mRNA, possibly through a mechanism involving sustained activation of MAPK and PI3K. These results reveal the existence of highly responsive, transient transcriptional regulatory mechanisms that differentially modulate NRG1 isoform expression as a function of extracellular and intracellular signaling cascades and mediated by neurotrophic factors and axon-target interactions. Copyright © 2015 Elsevier Inc. All rights reserved.

Tackling Glaucoma from within the Brain: An Unfortunate Interplay of BDNF and TrkB

PubMed Central

Dekeyster, Eline; Geeraerts, Emiel; Buyens, Tom; Van den Haute, Chris; Baekelandt, Veerle; De Groef, Lies; Salinas-Navarro, Manuel; Moons, Lieve

2015-01-01

According to the neurotrophin deprivation hypothesis, diminished retrograde delivery of neurotrophic support during an early stage of glaucoma pathogenesis is one of the main triggers that induce retinal ganglion cell (RGC) degeneration. Therefore, interfering with neurotrophic signaling seems an attractive strategy to achieve neuroprotection. Indeed, exogenous neurotrophin administration to the eye has been shown to reduce loss of RGCs in animal models of glaucoma; however, the neuroprotective effect was mostly insufficient for sustained RGC survival. We hypothesized that treatment at the level of neurotrophin-releasing brain areas might be beneficial, as signaling pathways activated by target-derived neurotrophins are suggested to differ from pathways that are initiated at the soma membrane. In our study, first, the spatiotemporal course of RGC degeneration was characterized in mice subjected to optic nerve crush (ONC) or laser induced ocular hypertension (OHT). Subsequently, the well-known neurotrophin brain-derived neurotrophic factor (BDNF) was chosen as the lead molecule, and the levels of BDNF and its high-affinity receptor, tropomyosin receptor kinase B (TrkB), were examined in the mouse retina and superior colliculus (SC) upon ONC and OHT. Both models differentially influenced BDNF and TrkB levels. Next, we aimed for RGC protection through viral vector-mediated upregulation of collicular BDNF, thought to boost the retrograde neurotrophin delivery. Although the previously reported temporary neuroprotective effect of intravitreally delivered recombinant BDNF was confirmed, viral vector-induced BDNF overexpression in the SC did not result in protection of the RGCs in the glaucoma models used. These findings most likely relate to decreased neurotrophin responsiveness upon vector-mediated BDNF overexpression. Our results highlight important insights concerning the complexity of neurotrophic factor treatments that should surely be considered in future neuroprotective strategies. PMID:26560713

Science Planning for Multi-Spacecraft Coordinated Observations

NASA Technical Reports Server (NTRS)

Maks, Lori; Fishman, Mark; Pell, Vince; Obenschain, Arthur F. (Technical Monitor)

2002-01-01

Fulfilling the promise of an era of great observatories, NASA now has more than three space-based astronomical telescopes operating in different wavebands. This situation provides astronomers with a unique opportunity to simultaneously observe with multiple observatories. Yet scheduling multiple observatories simultaneously is highly inefficient when compared to single observatory observations. Thus, programs using multiple observatories are limited not due to scientific restrictions, but due to operational inefficiencies. Each year, a number of proposals are accepted by a space-based observatory for conduction of astronomical observations and gathering of science data for the study of galactic events. Since each space-based observatory uses a set of instruments designed to operate in specific energy regions, most such studies are conducted by submitting observation proposals to multiple observatories, with requests to coordinate among themselves. To assure that the proposed observations can be scheduled, each observatory's staff has to check that the observations are valid and meet all the constraints for their own observatory; in addition, they have to verify that the observations satisfy the constraints of the other observatories. Thus, coordinated observations require painstaking manual collaboration among the observatory staff at each observatory. In order to exploit new paradigms for observatory operation, the Goddard Space Flight Center's Advanced Architectures and Automation Branch has developed a prototype tool called the Visual Observation Layout Tool (VOLT). The main objective of VOLT is to provide a visual tool to automate the science planning of coordinated observations for multiple spacecraft, as well as to increase the scheduling probability of observations. However, VOLT is also useful for single observatory planning to optimize observatory control. Three space-based missions are interested in using VOLT (the Hubble Space Telescope, the Chandra X-Ray Observatory, and the Far Ultraviolet Spectroscopic Explorer). The VOLT team members have collaborated with these missions to gather requirements and obtain feedback on their mission planning processes. VOLT has been developed as a cross-platform Java client application for use by scientists and observatory science planning staff to visualize scheduling options and constraints. It also supports a lightweight graphical user interface for remote viewing via a Web front end. Additionally, it uniquely supports the ability to interact with multiple, diverse scheduling packages in order to determine windows of opportunity for observations and visually portray the constraints of each observation request. VOLT enables science data capture scenarios which are currently either impossible, or which require extensive time and manpower to coordinate amongst multiple observatories. it supports early detection of planning conflicts by generating coordinated solutions based on observatory schedulability and constraints. The project development approach has included frequent prototype demonstrations to our interested missions to obtain feedback after each release of the software. We will present an overview of our lessons learned in infusing the VOLT tool into the operations of the missions we have collaborated with and a brief demonstration of the software.

Protecting Neural Structures and Cognitive Function During Prolonged Space Flight by Targeting the Brain Derived Neurotrophic Factor Molecular Network

NASA Technical Reports Server (NTRS)

Schmidt, M. A.; Goodwin, T. J.

2014-01-01

Brain derived neurotrophic factor (BDNF) is the main activity-dependent neurotrophin in the human nervous system. BDNF is implicated in production of new neurons from dentate gyrus stem cells (hippocampal neurogenesis), synapse formation, sprouting of new axons, growth of new axons, sprouting of new dendrites, and neuron survival. Alterations in the amount or activity of BDNF can produce significant detrimental changes to cortical function and synaptic transmission in the human brain. This can result in glial and neuronal dysfunction, which may contribute to a range of clinical conditions, spanning a number of learning, behavioral, and neurological disorders. There is an extensive body of work surrounding the BDNF molecular network, including BDNF gene polymorphisms, methylated BDNF gene promoters, multiple gene transcripts, varied BDNF functional proteins, and different BDNF receptors (whose activation differentially drive the neuron to neurogenesis or apoptosis). BDNF is also closely linked to mitochondrial biogenesis through PGC-1alpha, which can influence brain and muscle metabolic efficiency. BDNF AS A HUMAN SPACE FLIGHT COUNTERMEASURE TARGET Earth-based studies reveal that BDNF is negatively impacted by many of the conditions encountered in the space environment, including oxidative stress, radiation, psychological stressors, sleep deprivation, and many others. A growing body of work suggests that the BDNF network is responsive to a range of diet, nutrition, exercise, drug, and other types of influences. This section explores the BDNF network in the context of 1) protecting the brain and nervous system in the space environment, 2) optimizing neurobehavioral performance in space, and 3) reducing the residual effects of space flight on the nervous system on return to Earth

Association of Lipid Peroxidation and Brain-Derived Neurotrophic Factor with Executive Function in Adolescent Bipolar Disorder.

PubMed

Newton, Dwight F; Naiberg, Melanie R; Andreazza, Ana C; Scola, Gustavo; Dickstein, Daniel P; Goldstein, Benjamin I

2017-02-01

Executive dysfunction is common and impairing in youth bipolar disorder (BD), and oxidative stress (OS) and brain-derived neurotrophic factor (BDNF) have been implicated in executive deficits of adult BD. This study aimed to determine the association between OS and executive dysfunction in BD adolescents and the influence of BDNF on this association. Serum levels of lipid hydroperoxides (LPH) and 4-hydroxy-2-nonenal (4-HNE) and BDNF levels were measured in 29 BD and 25 control adolescents. The intra-extra-dimensional (IED) set-shifting task assessed executive function. Lower IED scores indicated better performance. High and low BDNF subgroups were defined by median split. IED Z-scores were impaired in the BD group compared to controls, whereas biomarker levels were not significantly different between groups. LPH-BDNF correlations were significantly different between BD and controls (Z = 2.046, p = 0.041). In high BDNF BD subjects, LPH was significantly positively correlated with IED completed stage trials (ρ = 0.755, p = 0.001) and pre-extra-dimensional shift errors (ρ = 0.588, p = 0.017). Correlations were opposite in controls. In a linear model, LPH, BDNF, and the LPH-BDNF interaction each significantly explained variance of IED total trials (adjusted) (model r 2  = 0.187, F = 2.811, p = 0.035). There is a negative association between LPH and executive function in BD adolescents, which may be modulated by BDNF. LPH and BDNF may be useful biomarkers of executive function in BD. These findings highlight the importance of examining multiple peripheral biomarkers in relation to cognitive functions in BD adolescents. Future studies should explore these factors in longitudinal designs to determine the directionality of observed associations.

Production of high quality brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) RNA from isolated populations of rat spinal cord motor neurons obtained by Laser Capture Microdissection (LCM).

PubMed

Mehta, Prachi; Premkumar, Brian; Morris, Renée

2016-08-03

The mammalian central nervous system (CNS) is composed of multiple cellular elements, making it challenging to segregate one particular cell type to study their gene expression profile. For instance, as motor neurons represent only 5-10% of the total cell population of the spinal cord, meaningful transcriptional analysis on these neurons is almost impossible to achieve from homogenized spinal cord tissue. A major challenge faced by scientists is to obtain good quality RNA from small amounts of starting material. In this paper, we used Laser Capture Microdissection (LCM) techniques to identify and isolate spinal cord motor neurons. The present analysis revealed that perfusion with paraformaldehyde (PFA) does not alter RNA quality. RNA integrity numbers (RINs) of tissue samples from rubrospinal tract (RST)-transected, intact spinal cord or from whole spinal cord homogenate were all above 8, which indicates intact, high-quality RNA. Levels of mRNA for brain-derived neurotrophic factor (BDNF) or for its tropomyosin receptor kinase B (TrkB) were not affected by rubrospinal tract (RST) transection, a surgical procedure that deprive motor neurons from one of their main supraspinal input. The isolation of pure populations of neurons with LCM techniques allows for robust transcriptional characterization that cannot be achieved with spinal cord homogenates. Such preparations of pure population of motor neurons will provide valuable tools to advance our understanding of the molecular mechanisms underlying spinal cord injury and neuromuscular diseases. In the near future, LCM techniques might be instrumental to the success of gene therapy for these debilitating conditions. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Postnatal Development of Brain-Derived Neurotrophic Factor (BDNF) and Tyrosine Protein Kinase B (TrkB) Receptor Immunoreactivity in Multiple Brain Stem Respiratory-Related Nuclei of the Rat

PubMed Central

Liu, Qiuli; Wong-Riley, Margaret T.T.

2013-01-01

Previously, we found a transient imbalance between suppressed excitation and enhanced inhibition in the respiratory network of the rat around postnatal days (P) 12–13, a critical period when the hypoxic ventilatory response is at its weakest. The mechanism underlying the imbalance is poorly understood. Brain-derived neurotrophic factor (BDNF) and its tyrosine protein kinase B (TrkB) receptors are known to potentiate glutamatergic and attenuate gamma-aminobutyric acid (GABA)ergic neurotransmission, and BDNF is essential for respiratory development. We hypothesized that the excitation-inhibition imbalance during the critical period stemmed from a reduced expression of BDNF and TrkB at that time within respiratory-related nuclei of the brain stem. An in-depth, semiquantitative immunohistochemical study was undertaken in seven respiratory-related brain stem nuclei and one nonrespiratory nucleus in P0–21 rats. The results indicate that the expressions of BDNF and TrkB: 1) in the pre-Bötzinger complex, nucleus ambiguus, commissural and ventrolateral subnuclei of solitary tract nucleus, and retrotrapezoid nucleus/parafacial respiratory group were significantly reduced at P12, but returned to P11 levels by P14; 2) in the lateral paragigantocellular nucleus and parapyramidal region were increased from P0 to P7, but were strikingly reduced at P10 and plateaued thereafter; and 3) in the nonrespiratory cuneate nucleus showed a gentle plateau throughout the first 3 post-natal weeks, with only a slight decline of BDNF expression after P11. Thus, the significant downregulation of both BDNF and TrkB in respiratory-related nuclei during the critical period may form the basis of, or at least contribute to, the inhibitory-excitatory imbalance within the respiratory network during this time. PMID:22678720

The Impact of Aerobic Exercise on Brain-Derived Neurotrophic Factor and Neurocognition in Individuals With Schizophrenia: A Single-Blind, Randomized Clinical Trial

PubMed Central

Kimhy, David; Vakhrusheva, Julia; Bartels, Matthew N.; Armstrong, Hilary F.; Ballon, Jacob S.; Khan, Samira; Chang, Rachel W.; Hansen, Marie C.; Ayanruoh, Lindsey; Lister, Amanda; Castrén, Eero; Smith, Edward E.; Sloan, Richard P.

2015-01-01

Individuals with schizophrenia display substantial neurocognitive deficits for which available treatments offer only limited benefits. Yet, findings from studies of animals, clinical and nonclinical populations have linked neurocognitive improvements to increases in aerobic fitness (AF) via aerobic exercise training (AE). Such improvements have been attributed to up-regulation of brain-derived neurotrophic factor (BDNF). However, the impact of AE on neurocognition, and the putative role of BDNF, have not been investigated in schizophrenia. Employing a proof-of-concept, single-blind, randomized clinical trial design, 33 individuals with schizophrenia were randomized to receive standard psychiatric treatment (n = 17; “treatment as usual”; TAU) or attend a 12-week AE program (n = 16) utilizing active-play video games (Xbox 360 Kinect) and traditional AE equipment. Participants completed assessments of AF (indexed by VO2 peak ml/kg/min), neurocognition (MATRICS Consensus Cognitive Battery), and serum-BDNF before and after and 12-week period. Twenty-six participants (79%) completed the study. At follow-up, the AE participants improved their AF by 18.0% vs a −0.5% decline in the TAU group (P = .002) and improved their neurocognition by 15.1% vs −2.0% decline in the TAU group (P = .031). Hierarchical multiple regression analyses indicated that enhancement in AF and increases in BDNF predicted 25.4% and 14.6% of the neurocognitive improvement variance, respectively. The results indicate AE is effective in enhancing neurocognitive functioning in people with schizophrenia and provide preliminary support for the impact of AE-related BDNF up-regulation on neurocognition in this population. Poor AF represents a modifiable risk factor for neurocognitive dysfunction in schizophrenia for which AE training offer a safe, nonstigmatizing, and side-effect-free intervention. PMID:25805886

The brain-derived neurotrophic factor Val66Met polymorphism is associated with reduced functional magnetic resonance imaging activity in the hippocampus and increased use of caudate nucleus-dependent strategies in a human virtual navigation task

PubMed Central

Banner, Harrison; Bhat, Venkataramana; Etchamendy, Nicole; Joober, Ridha; Bohbot, Véronique D

2011-01-01

Multiple memory systems are involved in parallel processing of spatial information during navigation. A series of studies have distinguished between hippocampus-dependent ‘spatial’ navigation, which relies on knowledge of the relationship between landmarks in one’s environment to build a cognitive map, and habit-based ‘response’ learning, which requires the memorization of a series of actions and is mediated by the caudate nucleus. Studies have demonstrated that people spontaneously use one of these two alternative navigational strategies with almost equal frequency to solve a given navigation task, and that strategy correlates with functional magnetic resonance imaging (fMRI) activity and grey matter density. Although there is evidence for experience modulating grey matter in the hippocampus, genetic contributions may also play an important role in the hippocampus and caudate nucleus. Recently, the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene has emerged as a possible inhibitor of hippocampal function. We have investigated the role of the BDNF Val66Met polymorphism on virtual navigation behaviour and brain activation during an fMRI navigation task. Our results demonstrate a genetic contribution to spontaneous strategies, where ‘Met’ carriers use a response strategy more frequently than individuals homozygous for the ‘Val’ allele. Additionally, we found increased hippocampal activation in the Val group relative to the Met group during performance of a virtual navigation task. Our results support the idea that the BDNF gene with the Val66Met polymorphism is a novel candidate gene involved in determining spontaneous strategies during navigation behaviour. PMID:21255124

Effects of the Brain-Derived Neurotrophic Factor Val66Met polymorphism and resting brain functional connectivity on individual differences in tactile cognitive performance in healthy young adults.

PubMed

Yang, Xuejuan; Xu, Ziliang; Liu, Lin; Liu, Peng; Sun, Jinbo; Jin, Lingmin; Zhu, Yuanqiang; Fei, Ningbo; Qin, Wei

2017-07-28

Cognitive processes involve input from multiple sensory modalities and obvious differences in the level of cognitive function can be observed between individuals. Evidence to date understanding the biological basis of tactile cognitive variability, however, is limited compared with other forms of sensory cognition. Data from auditory and visual cognition research suggest that variations in both genetics and intrinsic brain function might contribute to individual differences in tactile cognitive performance. In the present study, by using the tactual performance test (TPT), a widely used neuropsychological assessment tool, we investigated the effects of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and resting-state brain functional connectivity (FC) on interindividual variability in TPT performance in healthy, young Chinese adults. Our results showed that the BDNF genotypes and resting-state FC had significant effects on the variability in TPT performance, together accounting for 32.5% and 19.1% of the variance on TPT total score and Memory subitem score respectively. Having fewer Met alleles, stronger anticorrelations between left posterior superior temporal gyrus and somatosensory areas (right postcentral gyrus and right parietal operculum cortex), and greater positive correlation between left parietal operculum cortex and left central opercular cortex, all correspond with better performance of TPT task. And FC between left parietal operculum cortex and left central opercular cortex might be a mediator of the relationship between BDNF genotypes and Memory subitem score. These data demonstrate a novel contribution of intrinsic brain function to tactile cognitive capacity, and further confirm the genetic basis of tactile cognition. Our findings might also explain the interindividual differences in cognitive ability observed in those who are blind and/or deaf from a new perspective. Copyright © 2017. Published by Elsevier Ltd.

Impact of acamprosate on behavior and brain-derived neurotrophic factor: an open-label study in youth with fragile X syndrome.

PubMed

Erickson, Craig A; Wink, Logan K; Ray, Balmiki; Early, Maureen C; Stiegelmeyer, Elizabeth; Mathieu-Frasier, Lauren; Patrick, Vanessa; Lahiri, Debomoy K; McDougle, Christopher J

2013-07-01

Fragile X syndrome (FXS) is an inherited form of developmental disability and a single gene cause of autism. As a disorder with increasingly understood pathophysiology, FXS is a model form of developmental disability for targeted drug development efforts. Preclinical animal model findings have focused targeted drug treatment development in FXS on an imbalance between excessive glutamate and deficient gamma-aminobutyric acid (GABA) neurotransmission. We conducted a prospective open-label 10-week trial of acamprosate in 12 youth aged 6-17 years (mean age: 11.9 years) with FXS. Acamprosate use (mean dose: 1,054  ±  422 mg/day) was associated with treatment response (defined by a Clinical Global Impressions Improvement (CGI-I) scale score of "very much improved" or "much improved") in nine of 12 (75 %) subjects. Improvement was noted in social behavior and inattention/hyperactivity using multiple standard behavioral outcome measures. No significant adverse effects or changes in vital signs, including weight or laboratory measures, occurred during treatment with acamprosate. Additionally, pre- and post-treatment blood biomarker analyses looking at brain-derived neurotrophic factor (BDNF) levels found a significant increase in BDNF with treatment. In our pilot sample, treatment response did not correlate with change in BDNF with treatment. Acamprosate was generally safe and well tolerated and was associated with a significant improvement in social behavior and a reduction in inattention/hyperactivity. The increase in BDNF that occurred with treatment may be a useful pharmacodynamic marker in future acamprosate studies. Given these findings, a double-blind, placebo-controlled study of acamprosate in youth with FXS is warranted.

Explore the Features of Brain-Derived Neurotrophic Factor in Mood Disorders

PubMed Central

Yeh, Fan-Chi; Kao, Chung-Feng; Kuo, Po-Hsiu

2015-01-01

Objectives Brain-derived neurotrophic factor (BDNF) plays important roles in neuronal survival and differentiation; however, the effects of BDNF on mood disorders remain unclear. We investigated BDNF from the perspective of various aspects of systems biology, including its molecular evolution, genomic studies, protein functions, and pathway analysis. Methods We conducted analyses examining sequences, multiple alignments, phylogenetic trees and positive selection across 12 species and several human populations. We summarized the results of previous genomic and functional studies of pro-BDNF and mature-BDNF (m-BDNF) found in a literature review. We identified proteins that interact with BDNF and performed pathway-based analysis using large genome-wide association (GWA) datasets obtained for mood disorders. Results BDNF is encoded by a highly conserved gene. The chordate BDNF genes exhibit an average of 75% identity with the human gene, while vertebrate orthologues are 85.9%-100% identical to human BDNF. No signs of recent positive selection were found. Associations between BDNF and mood disorders were not significant in most of the genomic studies (e.g., linkage, association, gene expression, GWA), while relationships between serum/plasma BDNF level and mood disorders were consistently reported. Pro-BDNF is important in the response to stress; the literature review suggests the necessity of studying both pro- and m-BDNF with regard to mood disorders. In addition to conventional pathway analysis, we further considered proteins that interact with BDNF (I-Genes) and identified several biological pathways involved with BDNF or I-Genes to be significantly associated with mood disorders. Conclusions Systematically examining the features and biological pathways of BDNF may provide opportunities to deepen our understanding of the mechanisms underlying mood disorders. PMID:26091093

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pachuilo, Andrew R; Ragan, Eric; Goodall, John R

Visualization tools can take advantage of multiple coordinated views to support analysis of large, multidimensional data sets. Effective design of such views and layouts can be challenging, but understanding users analysis strategies can inform design improvements. We outline an approach for intelligent design configuration of visualization tools with multiple coordinated views, and we discuss a proposed software framework to support the approach. The proposed software framework could capture and learn from user interaction data to automate new compositions of views and widgets. Such a framework could reduce the time needed for meta analysis of the visualization use and lead tomore » more effective visualization design.« less

Plotting Points: Implications of "Over and Up" on Students' Covariational Reasoning

ERIC Educational Resources Information Center

Frank, Kristin M.

2016-01-01

In this study I investigate Saldanha and Thompson's (1998) claim that conceptualizing a coordinate pair in the Cartesian coordinate system as a multiplicative object, a way to unite two quantities' values, supports students in conceptualizing graphs as emergent representations of how two quantities' values change together. I presented three…

Technology Leaders Wanted: Acknowledging the Leadership Role of a Technology Coordinator

ERIC Educational Resources Information Center

Sugar, William; Holloman, Harold

2009-01-01

Technology currently plays a crucial role in impacting teaching practices within schools. Similarly, a technology coordinator performs several tasks within a school environment and plays multiple roles that influence teaching and learning each day. Described as a "position with a protocol," Frazier and Bailey (2004) noted that effective technology…

Stages in Constructing and Coordinating Units Additively and Multiplicatively (Part 2)

ERIC Educational Resources Information Center

Ulrich, Catherine

2016-01-01

This is the second of a two-part article that presents a theory of unit construction and coordination that underlies radical constructivist empirical studies of student learning ranging from young students' counting strategies to high school students' algebraic reasoning. In Part I, I discussed the formation of arithmetical units and composite…

Stages in Constructing and Coordinating Units Additively and Multiplicatively (Part 1)

ERIC Educational Resources Information Center

Ulrich, Catherine

2015-01-01

This is the first of a two-part article that presents a theory of unit construction and coordination that underlies radical constructivist empirical studies of student learning ranging from young students' counting strategies to high school students' algebraic reasoning. My explanation starts with the formation of arithmetical units, which presage…

Catalog of Non-Stellar Objects

DTIC Science & Technology

1977-09-12

multiplication with the matrix S", /l 0 " 0 V S" =10 cose -sine , (la) \\0 sine cose/ where e is the 1950.0 obliquity of the ecliptic , viz...helicocentric rectangular ecliptic coordinates. Let these be (x’", y"’, zŕ) = r;1". Then heliocentric rectangular equatorial coordinates are obtained by

Coordination of ScO+ and YO+ by multiple Ar, Kr, and Xe atoms in noble gas matrixes: a matrix isolation infrared spectroscopic and theoretical study.

PubMed

Zhao, Yanying; Gong, Yu; Chen, Mohua; Ding, Chuanfan; Zhou, Mingfei

2005-12-29

The combination of matrix isolation infrared spectroscopic and quantum chemical calculation results provide strong evidence that scandium and yttrium monoxide cations, ScO+ and YO+, coordinate multiple noble gas atoms in forming noble gas complexes. The results showed that ScO+ coordinates five Ar, Kr, or Xe atoms, and YO+ coordinates six Ar or Kr and five Xe atoms in solid noble gas matrixes. Hence, the ScO+ and YO+ cations trapped in solid noble gas matrixes should be regarded as the [ScO(Ng)5]+ (Ng = Ar, Kr, or Xe), [YO(Ng)6]+ (Ng = Ar or Kr) or [YO(Xe)5]+ complexes. Experiments with dilute krypton or xenon in argon or krypton in xenon produced new IR bands, which are due to the stepwise formation of the [ScO(Ar)(5-n)(Kr)n]+, [ScO(Kr)(5-n)(Xe)n]+ (n = 1-5), [YO(Ar)(6-n)(Kr)n]+ (n = 1-6), and [YO(Ar)(6-n)(Xe)n]+ (n = 1-4) complexes.

Optimal wide-area monitoring and nonlinear adaptive coordinating neurocontrol of a power system with wind power integration and multiple FACTS devices.

PubMed

Qiao, Wei; Venayagamoorthy, Ganesh K; Harley, Ronald G

2008-01-01

Wide-area coordinating control is becoming an important issue and a challenging problem in the power industry. This paper proposes a novel optimal wide-area coordinating neurocontrol (WACNC), based on wide-area measurements, for a power system with power system stabilizers, a large wind farm and multiple flexible ac transmission system (FACTS) devices. An optimal wide-area monitor (OWAM), which is a radial basis function neural network (RBFNN), is designed to identify the input-output dynamics of the nonlinear power system. Its parameters are optimized through particle swarm optimization (PSO). Based on the OWAM, the WACNC is then designed by using the dual heuristic programming (DHP) method and RBFNNs, while considering the effect of signal transmission delays. The WACNC operates at a global level to coordinate the actions of local power system controllers. Each local controller communicates with the WACNC, receives remote control signals from the WACNC to enhance its dynamic performance and therefore helps improve system-wide dynamic and transient performance. The proposed control is verified by simulation studies on a multimachine power system.

ISECG Global Exploration Roadmap: A Stepwise Approach to Deep Space Exploration

NASA Technical Reports Server (NTRS)

Martinez, Roland; Goodliff, Kandyce; Whitley, Ryan

2013-01-01

In 2011, ISECG released the Global Exploration Roadmap (GER), advancing the "Global Exploration Strategy: The Framework for Coordination" by articulating the perspectives of participating agencies on exploration goals and objectives, mission scenarios, and coordination of exploration preparatory activities. The GER featured a stepwise development and demonstration of capabilities ultimately required for human exploration of Mars. In 2013 the GER was updated to reflect the ongoing evolution of agency's exploration policies and plans, informed by individual agency and coordinated analysis activities that are relevant to various elements of the GER framework as well as coordinated stakeholder engagement activities. For this release of version 2 of the GER in the mid 2013 timeframe, a modified mission scenario is presented, more firmly reflecting the importance of a stepwise evolution of critical capabilities provided by multiple partners necessary for executing increasingly complex missions to multiple destinations and leading to human exploration of Mars. This paper will describe the updated mission scenario, the changes since the release of version 1, the mission themes incorporated into the scenario, and risk reduction for Mars missions provided by exploration at various destinations.

Care coordination between convenient care clinics and healthcare homes.

PubMed

Carney Moore, Jeanne Marie; Dolansky, Mary; Hudak, Christine; Kenneley, Irena

2015-05-01

Patient care coordination is foundational to high-quality health care and is a national priority. Since its inception, convenient health care has been criticized for its potential to decrease patient care coordination. The purpose of this study is to investigate care coordination between convenient care clinics and healthcare homes. The care coordination practices of Minute Clinic, which represents over 40% of the convenient care industry, were studied. Patient identification of healthcare homes and consent to transmit visit records were abstracted from the health records of 1,014,249 patients dated July 1 to December 31, 2012. The completeness of record content and timeliness of record transmission were assessed by means of interviewing Minute Clinic's Director of Quality and reviewing patient electronic health records. Minute Clinic attempts to coordinate care with healthcare homes, but opportunities for improved care coordination exist. Increased vigilance on the part of providers, patients, and healthcare systems is needed to mitigate barriers to care coordination. Future research is needed to examine care coordination from multiple convenient care operators and explore how to increase care coordination with healthcare homes. ©2014 American Association of Nurse Practitioners.

A New Drug Design Targeting the Adenosinergic System for Huntington's Disease

PubMed Central

Lin, Jiun-Tsai; Lin, Chia-I; Liu, Eric Minwei; Lin, Chun-Jung; Chen, Wan-Ping; Shen, Yuh-Chiang; Chen, Hui-Mei; Chen, Jhih-Bin; Lai, Hsing-Lin; Yang, Chieh-Wen; Chiang, Ming-Chang; Wu, Yu-Shuo; Chang, Chen; Chen, Jiang-Fan; Fang, Jim-Min; Lin, Yun-Lian; Chern, Yijuang

2011-01-01

Background Huntington's disease (HD) is a neurodegenerative disease caused by a CAG trinucleotide expansion in the Huntingtin (Htt) gene. The expanded CAG repeats are translated into polyglutamine (polyQ), causing aberrant functions as well as aggregate formation of mutant Htt. Effective treatments for HD are yet to be developed. Methodology/Principal Findings Here, we report a novel dual-function compound, N 6-(4-hydroxybenzyl)adenine riboside (designated T1-11) which activates the A2AR and a major adenosine transporter (ENT1). T1-11 was originally isolated from a Chinese medicinal herb. Molecular modeling analyses showed that T1-11 binds to the adenosine pockets of the A2AR and ENT1. Introduction of T1-11 into the striatum significantly enhanced the level of striatal adenosine as determined by a microdialysis technique, demonstrating that T1-11 inhibited adenosine uptake in vivo. A single intraperitoneal injection of T1-11 in wildtype mice, but not in A2AR knockout mice, increased cAMP level in the brain. Thus, T1-11 enters the brain and elevates cAMP via activation of the A2AR in vivo. Most importantly, addition of T1-11 (0.05 mg/ml) to the drinking water of a transgenic mouse model of HD (R6/2) ameliorated the progressive deterioration in motor coordination, reduced the formation of striatal Htt aggregates, elevated proteasome activity, and increased the level of an important neurotrophic factor (brain derived neurotrophic factor) in the brain. These results demonstrate the therapeutic potential of T1-11 for treating HD. Conclusions/Significance The dual functions of T1-11 enable T1-11 to effectively activate the adenosinergic system and subsequently delay the progression of HD. This is a novel therapeutic strategy for HD. Similar dual-function drugs aimed at a particular neurotransmitter system as proposed herein may be applicable to other neurotransmitter systems (e.g., the dopamine receptor/dopamine transporter and the serotonin receptor/serotonin transporter) and may facilitate the development of new drugs for other neurodegenerative diseases. PMID:21713039

A novel enteric neuron-glia coculture system reveals the role of glia in neuronal development.

PubMed

Le Berre-Scoul, Catherine; Chevalier, Julien; Oleynikova, Elena; Cossais, François; Talon, Sophie; Neunlist, Michel; Boudin, Hélène

2017-01-15

Unlike astrocytes in the brain, the potential role of enteric glial cells (EGCs) in the formation of the enteric neuronal circuit is currently unknown. To examine the role of EGCs in the formation of the neuronal network, we developed a novel neuron-enriched culture model from embryonic rat intestine grown in indirect coculture with EGCs. We found that EGCs shape axonal complexity and synapse density in enteric neurons, through purinergic- and glial cell line-derived neurotrophic factor-dependent pathways. Using a novel and valuable culture model to study enteric neuron-glia interactions, our study identified EGCs as a key cellular actor regulating neuronal network maturation. In the nervous system, the formation of neuronal circuitry results from a complex and coordinated action of intrinsic and extrinsic factors. In the CNS, extrinsic mediators derived from astrocytes have been shown to play a key role in neuronal maturation, including dendritic shaping, axon guidance and synaptogenesis. In the enteric nervous system (ENS), the potential role of enteric glial cells (EGCs) in the maturation of developing enteric neuronal circuit is currently unknown. A major obstacle in addressing this question is the difficulty in obtaining a valuable experimental model in which enteric neurons could be isolated and maintained without EGCs. We adapted a cell culture method previously developed for CNS neurons to establish a neuron-enriched primary culture from embryonic rat intestine which was cultured in indirect coculture with EGCs. We demonstrated that enteric neurons grown in such conditions showed several structural, phenotypic and functional hallmarks of proper development and maturation. However, when neurons were grown without EGCs, the complexity of the axonal arbour and the density of synapses were markedly reduced, suggesting that glial-derived factors contribute strongly to the formation of the neuronal circuitry. We found that these effects played by EGCs were mediated in part through purinergic P2Y 1 receptor- and glial cell line-derived neurotrophic factor-dependent pathways. Using a novel and valuable culture model to study enteric neuron-glia interactions, our study identified EGCs as a key cellular actor required for neuronal network maturation. © 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.

A novel enteric neuron–glia coculture system reveals the role of glia in neuronal development

PubMed Central

Le Berre‐Scoul, Catherine; Chevalier, Julien; Oleynikova, Elena; Cossais, François; Talon, Sophie; Neunlist, Michel

2016-01-01

Key points Unlike astrocytes in the brain, the potential role of enteric glial cells (EGCs) in the formation of the enteric neuronal circuit is currently unknown.To examine the role of EGCs in the formation of the neuronal network, we developed a novel neuron‐enriched culture model from embryonic rat intestine grown in indirect coculture with EGCs.We found that EGCs shape axonal complexity and synapse density in enteric neurons, through purinergic‐ and glial cell line‐derived neurotrophic factor‐dependent pathways.Using a novel and valuable culture model to study enteric neuron–glia interactions, our study identified EGCs as a key cellular actor regulating neuronal network maturation. Abstract In the nervous system, the formation of neuronal circuitry results from a complex and coordinated action of intrinsic and extrinsic factors. In the CNS, extrinsic mediators derived from astrocytes have been shown to play a key role in neuronal maturation, including dendritic shaping, axon guidance and synaptogenesis. In the enteric nervous system (ENS), the potential role of enteric glial cells (EGCs) in the maturation of developing enteric neuronal circuit is currently unknown. A major obstacle in addressing this question is the difficulty in obtaining a valuable experimental model in which enteric neurons could be isolated and maintained without EGCs. We adapted a cell culture method previously developed for CNS neurons to establish a neuron‐enriched primary culture from embryonic rat intestine which was cultured in indirect coculture with EGCs. We demonstrated that enteric neurons grown in such conditions showed several structural, phenotypic and functional hallmarks of proper development and maturation. However, when neurons were grown without EGCs, the complexity of the axonal arbour and the density of synapses were markedly reduced, suggesting that glial‐derived factors contribute strongly to the formation of the neuronal circuitry. We found that these effects played by EGCs were mediated in part through purinergic P2Y1 receptor‐ and glial cell line‐derived neurotrophic factor‐dependent pathways. Using a novel and valuable culture model to study enteric neuron–glia interactions, our study identified EGCs as a key cellular actor required for neuronal network maturation. PMID:27436013

The interrelationship of metabolic syndrome and neurodegenerative diseases with focus on brain-derived neurotrophic factor (BDNF): Kill two birds with one stone.

PubMed

Motamedi, Shima; Karimi, Isaac; Jafari, Fariba

2017-06-01

The brain-derived neurotrophic factor (BDNF) is involved in metabolic syndrome (MetS) and neurodegenerative diseases (NDD) like Alzheimer's disease, Huntington's disease, Parkinson's disease and depression. If one factor plays an essential role in the pathogenesis of two diseases, it can be concluded that there might be a common root in these two diseases, as well. This review was aimed to highlight the crucial roles of BDNF in the pathogenesis of MetS and NDD and to introduce sole prophylactic or therapeutic applications, BDNF gene therapy and BDFN administration, in controlling MetS and NDD.

Patient- and family-centered care coordination: a framework for integrating care for children and youth across multiple systems.

PubMed

2014-05-01

Understanding a care coordination framework, its functions, and its effects on children and families is critical for patients and families themselves, as well as for pediatricians, pediatric medical subspecialists/surgical specialists, and anyone providing services to children and families. Care coordination is an essential element of a transformed American health care delivery system that emphasizes optimal quality and cost outcomes, addresses family-centered care, and calls for partnership across various settings and communities. High-quality, cost-effective health care requires that the delivery system include elements for the provision of services supporting the coordination of care across settings and professionals. This requirement of supporting coordination of care is generally true for health systems providing care for all children and youth but especially for those with special health care needs. At the foundation of an efficient and effective system of care delivery is the patient-/family-centered medical home. From its inception, the medical home has had care coordination as a core element. In general, optimal outcomes for children and youth, especially those with special health care needs, require interfacing among multiple care systems and individuals, including the following: medical, social, and behavioral professionals; the educational system; payers; medical equipment providers; home care agencies; advocacy groups; needed supportive therapies/services; and families. Coordination of care across settings permits an integration of services that is centered on the comprehensive needs of the patient and family, leading to decreased health care costs, reduction in fragmented care, and improvement in the patient/family experience of care. Copyright © 2014 by the American Academy of Pediatrics.

[The role of neurotrophic factors in adaptational processes in the nervous system].

PubMed

Akoev, G N; Chalisova, N I

1995-08-01

Many of neurotrophic factors (NTF) promote the survival during development, growth and neurite differentiation of neurons. The most known NTF are nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophins-3,4,5. These factors increase the survival of peripheral sensory neurons and some central neurons. The NTF are produced by the target of neuronal proections including brain tissues. So the process of adaptation in the nervous system may be also connected with level of the NTF. Recently it is shown that the NTF level in the brain is changed by central nervous system deseases--epilepsy, Parcinson and Alcgeimer deseases. In this conditions NGF and BDNF mRNC expression and their receptors mRNC are increased. So NTF diffusion in intracellular space can provide the brain function regulation in normal and pathological conditions. Model of chronic epileptogenesis was in vitro. The organotypic coculture was used--the rat newborn hippocampus and chick embryo dorsal root ganglia. Veratridine (30 nM) added in culture media induced neuronal activity in hippocampus explants and the level of NTF in media cosequently rised. It was shown that neurite-stimulating effect was mediated by veratridine. This action was blocked by NGF-antybody treatment and due to NGF activity.

Intramuscular transplantation of bone marrow cells prolongs the lifespan of SOD1G93A mice and modulates expression of prognosis biomarkers of the disease.

PubMed

Rando, Amaya; Pastor, Diego; Viso-León, Mari Carmen; Martínez, Anna; Manzano, Raquel; Navarro, Xavier; Osta, Rosario; Martínez, Salvador

2018-04-06

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive muscle weakness, paralysis and death. There is no effective treatment for ALS and stem cell therapy has arisen as a potential therapeutic approach. SOD1 mutant mice were used to study the potential neurotrophic effect of bone marrow cells grafted into quadriceps femoris muscle. Bone marrow intramuscular transplants resulted in increased longevity with improved motor function and decreased motoneuron degeneration in the spinal cord. Moreover, the increment of the glial-derived neurotrophic factor and neurotrophin 4 observed in the grafted muscles suggests that this partial neuroprotective effect is mediated by neurotrophic factor release at the neuromuscular junction level. Finally, certain neurodegeneration and muscle disease-specific markers, which are altered in the SOD1 G93A mutant mouse and may serve as molecular biomarkers for the early detection of ALS in patients, have been studied with encouraging results. This work demonstrates that stem cell transplantation in the muscle prolonged the lifespan, increased motoneuron survival and slowed disease progression, which was also assessed by genetic expression analysis.

Neuroprotective Effects of Filgrastim in Rotenone-Induced Parkinson's Disease in Rats: Insights into its Anti-Inflammatory, Neurotrophic, and Antiapoptotic Effects.

PubMed

Azmy, Mariama S; Menze, Esther T; El-Naga, Reem N; Tadros, Mariane G

2018-01-11

All current treatments of Parkinson's disease (PD) focus on enhancing the dopaminergic effects and providing symptomatic relief; however, they cannot delay the disease progression. Filgrastim, a recombinant methionyl granulocyte colony-stimulating factor, demonstrated neuroprotection in many neurodegenerative and neurological diseases. This study aimed to assess the neuroprotective effects of filgrastim in rotenone-induced rat model of PD and investigate the potential underlying mechanisms of filgrastim actions. The effects of two doses of filgrastim (20 and 40 μg/kg) on spontaneous locomotion, catalepsy, body weight, histology, and striatal dopamine (DA) content, as well as tyrosine hydroxylase (TH) and α-synuclein expression, were evaluated. Then, the effective dose was further tested for its potential anti-inflammatory, neurotrophic, and antiapoptotic effects. Filgrastim (40 μg/kg) prevented rotenone-induced motor deficits, weight reduction, striatal DA depletion, and histological damage. Besides, it significantly inhibited rotenone-induced decrease in TH expression and increase in α-synuclein immunoreactivity in the midbrains and striata of the rats. These effects were associated with reduction of rotenone-induced neuroinflammation, apoptosis, and brain-derived neurotrophic factor depletion. Collectively, these results suggest that filgrastim might be a good candidate for management of PD.

Neuroendocrine and neurotrophic signaling in Huntington's disease: Implications for pathogenic mechanisms and treatment strategies.

PubMed

Bartlett, Danielle M; Cruickshank, Travis M; Hannan, Anthony J; Eastwood, Peter R; Lazar, Alpar S; Ziman, Mel R

2016-12-01

Huntington's disease (HD) is a fatal neurodegenerative disease caused by an extended polyglutamine tract in the huntingtin protein. Circadian, sleep and hypothalamic-pituitary-adrenal (HPA) axis disturbances are observed in HD as early as 15 years before clinical disease onset. Disturbances in these key processes result in increased cortisol and altered melatonin release which may negatively impact on brain-derived neurotrophic factor (BDNF) expression and contribute to documented neuropathological and clinical disease features. This review describes the normal interactions between neurotrophic factors, the HPA-axis and circadian rhythm, as indicated by levels of BDNF, cortisol and melatonin, and the alterations in these intricately balanced networks in HD. We also discuss the implications of these alterations on the neurobiology of HD and the potential to result in hypothalamic, circadian, and sleep pathologies. Measurable alterations in these pathways provide targets that, if treated early, may reduce degeneration of brain structures. We therefore focus here on the means by which multidisciplinary therapy could be utilised as a non-pharmaceutical approach to restore the balance of these pathways. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

The Metastable Brain

PubMed Central

Tognoli, Emmanuelle; Kelso, J. A. Scott

2014-01-01

Neural ensembles oscillate across a broad range of frequencies and are transiently coupled or “bound” together when people attend to a stimulus, perceive, think and act. This is a dynamic, self-assembling process, with parts of the brain engaging and disengaging in time. But how is it done? The theory of Coordination Dynamics proposes a mechanism called metastability, a subtle blend of integration and segregation. Tendencies for brain regions to express their individual autonomy and specialized functions (segregation, modularity) coexist with tendencies to couple and coordinate globally for multiple functions (integration). Although metastability has garnered increasing attention, it has yet to be demonstrated and treated within a fully spatiotemporal perspective. Here, we illustrate metastability in continuous neural and behavioral recordings, and we discuss theory and experiments at multiple scales suggesting that metastable dynamics underlie the real-time coordination necessary for the brain's dynamic cognitive, behavioral and social functions. PMID:24411730

Shared Authentic Leadership in Research Teams: Testing a Multiple Mediation Model.

PubMed

Guenter, Hannes; Gardner, William L; Davis McCauley, Kelly; Randolph-Seng, Brandon; Prabhu, Veena P

2017-12-01

Research teams face complex leadership and coordination challenges. We propose shared authentic leadership (SAL) as a timely approach to addressing these challenges. Drawing from authentic and functional leadership theories, we posit a multiple mediation model that suggests three mechanisms whereby SAL influences team effectiveness: shared mental models (SMM), team trust, and team coordination. To test our hypotheses, we collected survey data on leadership and teamwork within 142 research teams that recently published an article in a peer-reviewed management journal. The results indicate team coordination represents the primary mediating mechanism accounting for the relationship between SAL and research team effectiveness. While teams with high trust and SMM felt more successful and were more satisfied, they were less successful in publishing in high-impact journals. We also found the four SAL dimensions (i.e., self-awareness, relational transparency, balanced processing, and internalized moral perspective) to associate differently with team effectiveness.

Shared Authentic Leadership in Research Teams: Testing a Multiple Mediation Model

PubMed Central

Guenter, Hannes; Gardner, William L.; Davis McCauley, Kelly; Randolph-Seng, Brandon; Prabhu, Veena P.

2017-01-01

Research teams face complex leadership and coordination challenges. We propose shared authentic leadership (SAL) as a timely approach to addressing these challenges. Drawing from authentic and functional leadership theories, we posit a multiple mediation model that suggests three mechanisms whereby SAL influences team effectiveness: shared mental models (SMM), team trust, and team coordination. To test our hypotheses, we collected survey data on leadership and teamwork within 142 research teams that recently published an article in a peer-reviewed management journal. The results indicate team coordination represents the primary mediating mechanism accounting for the relationship between SAL and research team effectiveness. While teams with high trust and SMM felt more successful and were more satisfied, they were less successful in publishing in high-impact journals. We also found the four SAL dimensions (i.e., self-awareness, relational transparency, balanced processing, and internalized moral perspective) to associate differently with team effectiveness. PMID:29187779

Serum vitamin D and hippocampal gray matter volume in schizophrenia.

PubMed

Shivakumar, Venkataram; Kalmady, Sunil V; Amaresha, Anekal C; Jose, Dania; Narayanaswamy, Janardhanan C; Agarwal, Sri Mahavir; Joseph, Boban; Venkatasubramanian, Ganesan; Ravi, Vasanthapuram; Keshavan, Matcheri S; Gangadhar, Bangalore N

2015-08-30

Disparate lines of evidence including epidemiological and case-control studies have increasingly implicated vitamin D in the pathogenesis of schizophrenia. Vitamin D deficiency can lead to dysfunction of the hippocampus--a brain region hypothesized to be critically involved in schizophrenia. In this study, we examined for potential association between serum vitamin D level and hippocampal gray matter volume in antipsychotic-naïve or antipsychotic-free schizophrenia patients (n = 35). Serum vitamin D level was estimated using 25-OH vitamin D immunoassay. Optimized voxel-based morphometry was used to analyze 3-Tesla magnetic resonance imaging (MRI) (1-mm slice thickness). Ninety-seven percent of the schizophrenia patients (n = 34) had sub-optimal levels of serum vitamin D (83%, deficiency; 14%, insufficiency). A significant positive correlation was seen between vitamin D and regional gray matter volume in the right hippocampus after controlling for age, years of education and total intracranial volume (Montreal Neurological Institute (MNI) coordinates: x = 35, y = -18, z = -8; t = 4.34 pFWE(Corrected) = 0.018). These observations support a potential role of vitamin D deficiency in mediating hippocampal volume deficits, possibly through neurotrophic, neuroimmunomodulatory and glutamatergic effects. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Behavioral testing of mice exposed to intermediate frequency magnetic fields indicates mild memory impairment.

PubMed

Kumari, Kajal; Koivisto, Hennariikka; Viluksela, Matti; Paldanius, Kaisa M A; Marttinen, Mikael; Hiltunen, Mikko; Naarala, Jonne; Tanila, Heikki; Juutilainen, Jukka

2017-01-01

Human exposure to intermediate frequency magnetic fields (MF) is increasing due to applications like electronic article surveillance systems and induction heating cooking hobs. However, limited data is available on their possible health effects. The present study assessed behavioral and histopathological consequences of exposing mice to 7.5 kHz MF at 12 or 120 μT for 5 weeks. No effects were observed on body weight, spontaneous activity, motor coordination, level of anxiety or aggression. In the Morris swim task, mice in the 120 μT group showed less steep learning curve than the other groups, but did not differ from controls in their search bias in the probe test. The passive avoidance task indicated a clear impairment of memory over 48 h in the 120 μT group. No effects on astroglial activation or neurogenesis were observed in the hippocampus. The mRNA expression of brain-derived neurotrophic factor did not change but expression of the proinflammatory cytokine tumor necrosis factor alpha mRNA was significantly increased in the 120 μT group. These findings suggest that 7.5 kHz MF exposure may lead to mild learning and memory impairment, possibly through an inflammatory reaction in the hippocampus.

Multiple Coordination Patterns in Infant and Adult Vocalizations

PubMed Central

Abney, Drew H.; Warlaumont, Anne S.; Oller, D. Kimbrough; Wallot, Sebastian; Kello, Christopher T.

2017-01-01

The study of vocal coordination between infants and adults has led to important insights into the development of social, cognitive, emotional and linguistic abilities. We used an automatic system to identify vocalizations produced by infants and adults over the course of the day for fifteen infants studied longitudinally during the first two years of life. We measured three different types of vocal coordination: coincidence-based, rate-based, and cluster-based. Coincidence-based and rate-based coordination are established measures in the developmental literature. Cluster-based coordination is new and measures the strength of matching in the degree to which vocalization events occur in hierarchically nested clusters. We investigated whether various coordination patterns differ as a function of vocalization type, whether different coordination patterns provide unique information about the dynamics of vocal interaction, and how the various coordination patterns each relate to infant age. All vocal coordination patterns displayed greater coordination for infant speech-related vocalizations, adults adapted the hierarchical clustering of their vocalizations to match that of infants, and each of the three coordination patterns had unique associations with infant age. Altogether, our results indicate that vocal coordination between infants and adults is multifaceted, suggesting a complex relationship between vocal coordination and the development of vocal communication. PMID:29375276

Scan Patterns Predict Sentence Production in the Cross-Modal Processing of Visual Scenes

ERIC Educational Resources Information Center

Coco, Moreno I.; Keller, Frank

2012-01-01

Most everyday tasks involve multiple modalities, which raises the question of how the processing of these modalities is coordinated by the cognitive system. In this paper, we focus on the coordination of visual attention and linguistic processing during speaking. Previous research has shown that objects in a visual scene are fixated before they…

How Students Learn from Multiple Contexts and Definitions: Proper Time as a Coordination Class

ERIC Educational Resources Information Center

Levrini, Olivia; diSessa, Andrea A.

2008-01-01

This article provides an empirical analysis of a single classroom episode in which students reveal difficulties with the concept of proper time in special relativity but slowly make progress in improving their understanding. The theoretical framework used is "coordination class theory," which is an evolving model of concepts and conceptual change.…

Coordinated Monitoring Systems for Early Care and Education. OPRE Research Brief 2016-19

ERIC Educational Resources Information Center

Maxwell, Kelly; Sosinsky, Laura; Tout, Kathryn; Hegseth, Danielle

2016-01-01

Early care and education providers are subject to monitoring by multiple agencies and organizations. In this brief provides an overview of monitoring and the major early care and education monitoring systems. It then offers possible goals for a coordinated monitoring system and describes some approaches to addressing those goals. Eleven dimensions…

Temporal coordination and adaptation to rate change in music performance.

PubMed

Loehr, Janeen D; Large, Edward W; Palmer, Caroline

2011-08-01

People often coordinate their actions with sequences that exhibit temporal variability and unfold at multiple periodicities. We compared oscillator- and timekeeper-based accounts of temporal coordination by examining musicians' coordination of rhythmic musical sequences with a metronome that gradually changed rate at the end of a musical phrase (Experiment 1) or at the beginning of a phrase (Experiment 2). The rhythms contained events that occurred at the same periodic rate as the metronome and at half the period. Rate change consisted of a linear increase or decrease in intervals between metronome onsets. Musicians coordinated their performances better with a metronome that decreased than increased in tempo (as predicted by an oscillator model), at both beginnings and ends of musical phrases. Model performance was tested with an oscillator period or timekeeper interval set to the same period as the metronome (1:1 coordination) or half the metronome period (2:1 coordination). Only the oscillator model was able to predict musicians' coordination at both periods. These findings suggest that coordination is based on internal neural oscillations that entrain to external sequences.

Care Coordination for the Chronically Ill: Understanding the Patient's Perspective

PubMed Central

Maeng, Daniel D; Martsolf, Grant R; Scanlon, Dennis P; Christianson, Jon B

2012-01-01

Objective To identify factors associated with perception of care coordination problems among chronically ill patients. Methods Patient-level data were obtained from a random-digit dial telephone survey of adults with chronic conditions. The survey measured respondents' self-report of care coordination problems and level of patient activation, using the Patient Activation Measure (PAM-13). Logistic regression was used to assess association between respondents' self-report of care coordination problems and a set of patient characteristics. Results Respondents in the highest activation stage had roughly 30–40 percent lower odds of reporting care coordination problems compared to those in the lowest stage (p < .01). Respondents with multiple chronic conditions were significantly more likely to report coordination problems than those with hypertension only. Respondents' race/ethnicity, employment, insurance status, income, and length of illness were not significantly associated with self-reported care coordination problems. Conclusion We conclude that patient activation and complexity of chronic illness are strongly associated with patients' self-report of care coordination problems. Developing targeted strategies to improve care coordination around these patient characteristics may be an effective way to address the issue. PMID:22985032

A comparison of genetic variants between proficient low- and high-risk sport participants.

PubMed

Thomson, Cynthia J; Power, Rebecca J; Carlson, Scott R; Rupert, Jim L; Michel, Grégory

2015-01-01

Athletes participating in high-risk sports consistently report higher scores on sensation-seeking measures than do low-risk athletes or non-athletic controls. To determine whether genetic variants commonly associated with sensation seeking were over-represented in such athletes, proficient practitioners of high-risk (n = 141) and low-risk sports (n = 132) were compared for scores on sensation seeking and then genotyped at 33 polymorphic loci in 14 candidate genes. As expected, athletes participating in high-risk sports score higher on sensation seeking than did low-risk sport athletes (P < .01). Genotypes were associated with high-risk sport participation for two genes (stathmin, (P = .004) and brain-derived neurotrophic factor (P = .03)) as well as when demographically matched subsets of the sport cohorts were compared (P < .05); however, in all cases, associations did not survive correction for multiple testing.

Review: the role of vitamin D in nervous system health and disease.

PubMed

DeLuca, G C; Kimball, S M; Kolasinski, J; Ramagopalan, S V; Ebers, G C

2013-08-01

Vitamin D and its metabolites have pleomorphic roles in both nervous system health and disease. Animal models have been paramount in contributing to our knowledge and understanding of the consequences of vitamin D deficiency on brain development and its implications for adult psychiatric and neurological diseases. The conflation of in vitro, ex vivo, and animal model data provide compelling evidence that vitamin D has a crucial role in proliferation, differentiation, neurotrophism, neuroprotection, neurotransmission, and neuroplasticity. Vitamin D exerts its biological function not only by influencing cellular processes directly, but also by influencing gene expression through vitamin D response elements. This review highlights the epidemiological, neuropathological, experimental and molecular genetic evidence implicating vitamin D as a candidate in influencing susceptibility to a number of psychiatric and neurological diseases. The strength of evidence varies for schizophrenia, autism, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, and is especially strong for multiple sclerosis. © 2013 British Neuropathological Society.

Forced and voluntary exercises equally improve spatial learning and memory and hippocampal BDNF levels.

PubMed

Alomari, Mahmoud A; Khabour, Omar F; Alzoubi, Karem H; Alzubi, Mohammad A

2013-06-15

Multiple evidence suggest the importance of exercise for cognitive and brain functions. Few studies however, compared the behavioral and neural adaptations to force versus voluntary exercise training. Therefore, spatial learning and memory formation and brain-derived neurotrophic factor (BDNF) were examined in Wister male rats after 6 weeks of either daily forced swimming, voluntary running exercises, or sedentary. Learning capabilities and short, 5-hour, and long term memories improved (p<0.05) similarly in the exercise groups, without changes (p>0.05) in the sedentary. Likewise, both exercises resulted in increased (p<0.05) hippocampal BDNF level. The results suggest that forced and voluntary exercises can similarly enhance cognitive- and brain-related tasks, seemingly vie the BDNF pathway. These data further confirm the health benefits of exercise and advocate both exercise modalities to enhance behavioral and neural functions. Copyright © 2013 Elsevier B.V. All rights reserved.

Sensitivity to neurotoxic stress is not increased in progranulin-deficient mice.

PubMed

Petkau, Terri L; Zhu, Shanshan; Lu, Ge; Fernando, Sarah; Cynader, Max; Leavitt, Blair R

2013-11-01

Loss-of-function mutations in the progranulin (GRN) gene are a common cause of autosomal dominant frontotemporal lobar degeneration, a fatal and progressive neurodegenerative disorder common in people less than 65 years of age. In the brain, progranulin is expressed in multiple regions at varying levels, and has been hypothesized to play a neuroprotective or neurotrophic role. Four neurotoxic agents were injected in vivo into constitutive progranulin knockout (Grn(-/-)) mice and their wild-type (Grn(+/+)) counterparts to assess neuronal sensitivity to toxic stress. Administration of 3-nitropropionic acid, quinolinic acid, kainic acid, and pilocarpine induced robust and measurable neuronal cell death in affected brain regions, but no differential cell death was observed between Grn(+/+) and Grn(-/-) mice. Thus, constitutive progranulin knockout mice do not have increased sensitivity to neuronal cell death induced by the acute chemical models of neuronal injury used in this study. Copyright © 2013. Published by Elsevier Inc.

Multiple roles of HDAC inhibition in neurodegenerative conditions

PubMed Central

Chuang, De-Maw; Leng, Yan; Marinova, Zoya; Kim, Hyeon-Ju; Chiu, Chi-Tso

2009-01-01

Histone deacetylases (HDACs) play a key role in homeostasis of protein acetylation in histones and other proteins and in regulating fundamental cellular activities such as transcription. Imbalances in protein acetylation levels and dysfunctions in transcription are associated with a wide variety of brain disorders. Treatment with various HDAC inhibitors corrects these deficiencies and has emerged as a promising new strategy for therapeutic intervention in neurodegenerative diseases. Here, we review and discuss intriguing recent developments in the use of HDAC inhibitors to combat neurodegenerative conditions in cellular and disease models. HDAC inhibitors have neuroprotective, neurotrophic and anti-inflammatory properties, and improvements in neurological performance, learning/memory and other disease phenotypes are frequently seen in these models. We discuss the targets and mechanisms underlying these effects of HDAC inhibition and comment on the potential for some HDAC inhibitors to prove clinically effective in treating neurodegenerative disorders. PMID:19775759

Early Life Stress Effects on Glucocorticoid—BDNF Interplay in the Hippocampus

PubMed Central

Daskalakis, Nikolaos P.; De Kloet, Edo Ronald; Yehuda, Rachel; Malaspina, Dolores; Kranz, Thorsten M.

2015-01-01

Early life stress (ELS) is implicated in the etiology of multiple psychiatric disorders. Important biological effects of ELS are manifested in stress-susceptible regions of the hippocampus and are partially mediated by long-term effects on glucocorticoid (GC) and/or neurotrophin signaling pathways. GC-signaling mediates the regulation of stress response to maintain homeostasis, while neurotrophin signaling plays a key role in neuronal outgrowth and is crucial for axonal guidance and synaptic integrity. The neurotrophin and GC-signaling pathways co-exist throughout the central nervous system (CNS), particularly in the hippocampus, which has high expression levels of glucocorticoid-receptors (GR) and mineralocorticoid-receptors (MR) as well as brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase receptor B (TrkB). This review addresses the effects of ELS paradigms on GC- and BDNF-dependent mechanisms and their crosstalk in the hippocampus, including potential implications for the pathogenesis of common stress-related disorders. PMID:26635521

Coordination of multiple robot arms

NASA Technical Reports Server (NTRS)

Barker, L. K.; Soloway, D.

1987-01-01

Kinematic resolved-rate control from one robot arm is extended to the coordinated control of multiple robot arms in the movement of an object. The structure supports the general movement of one axis system (moving reference frame) with respect to another axis system (control reference frame) by one or more robot arms. The grippers of the robot arms do not have to be parallel or at any pre-disposed positions on the object. For multiarm control, the operator chooses the same moving and control reference frames for each of the robot arms. Consequently, each arm then moves as though it were carrying out the commanded motions by itself.

Design and Cosimulation of Hierarchical Architecture for Demand Response Control and Coordination

DOE PAGES

Bhattarai, Bishnu P.; Levesque, Martin; Bak-Jensen, Birgitte; ...

2016-12-07

Demand response (DR) plays a key role for optimum asset utilization and to avoid or delay the need of new infrastructure investment. However, coordinated execution of multiple DRs is desired to maximize the DR benefits. In this paper, we propose a hierarchical DR architecture (HDRA) to control and coordinate the performance of various DR categories such that the operation of every DR category is backed-up by time delayed action of the others. A reliable, cost-effective communication infrastructure based on ZigBee, WiMAX, and fibers is designed to facilitate the HDRA execution. The performance of the proposed HDRA is demonstrated from themore » power system and communication perspectives in a cosimulation environment applied to a 0.4 kV/400 kVA real distribution network considering electric vehicles as a potential DR resource (DRR). The power simulation is performed employing a real time digital simulator whereas the communication simulation is performed using OMNeT++. Finally, the HDRA performance demonstrated the maximum utilization of available DR potential by facilitating simultaneous execution of multiple DRs and enabling participation of single DRR for multiple grid applications.« less

Design and Cosimulation of Hierarchical Architecture for Demand Response Control and Coordination

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bhattarai, Bishnu P.; Levesque, Martin; Bak-Jensen, Birgitte

Demand response (DR) plays a key role for optimum asset utilization and to avoid or delay the need of new infrastructure investment. However, coordinated execution of multiple DRs is desired to maximize the DR benefits. In this paper, we propose a hierarchical DR architecture (HDRA) to control and coordinate the performance of various DR categories such that the operation of every DR category is backed-up by time delayed action of the others. A reliable, cost-effective communication infrastructure based on ZigBee, WiMAX, and fibers is designed to facilitate the HDRA execution. The performance of the proposed HDRA is demonstrated from themore » power system and communication perspectives in a cosimulation environment applied to a 0.4 kV/400 kVA real distribution network considering electric vehicles as a potential DR resource (DRR). The power simulation is performed employing a real time digital simulator whereas the communication simulation is performed using OMNeT++. Finally, the HDRA performance demonstrated the maximum utilization of available DR potential by facilitating simultaneous execution of multiple DRs and enabling participation of single DRR for multiple grid applications.« less

Coordinating an Autonomous Earth-Observing Sensorweb

NASA Technical Reports Server (NTRS)

Sherwood, Robert; Cichy, Benjamin; Tran, Daniel; Chien, Steve; Rabideau, Gregg; Davies, Ashley; Castano, Rebecca; frye, Stuart; Mandl, Dan; Shulman, Seth;

Coordinated Multiple Cadaver Use for Minimally Invasive Surgical Training

PubMed Central

Blaschko, Sarah D.; Brooks, H. Mark; Dhuy, S. Michael; Charest-Shell, Cynthia; Clayman, Ralph V.

2007-01-01

Background: The human cadaver remains the gold standard for anatomic training and is highly useful when incorporated into minimally invasive surgical training programs. However, this valuable resource is often not used to its full potential due to a lack of multidisciplinary cooperation. Herein, we propose the coordinated multiple use of individual cadavers to better utilize anatomical resources and potentiate the availability of cadaver training. Methods: Twenty-two postgraduate surgeons participated in a robot-assisted surgical training course that utilized shared cadavers. All participants completed a Likert 4-scale satisfaction questionnaire after their training session. Cadaveric tissue quality and the quality of the training session related to this material were assessed. Results: Nine participants rated the quality of the cadaveric tissue as excellent, 7 as good, 5 as unsatisfactory, and 1 as poor. Overall, 72% of participants who operated on a previously used cadaver were satisfied with their training experience and did not perceive the previous use deleterious to their training. Conclusion: The coordinated use of cadavers, which allows for multiple cadaver use for different teaching sessions, is an excellent training method that increases availability of human anatomical material for minimally invasive surgical training. PMID:18237501

Fusagene vectors: a novel strategy for the expression of multiple genes from a single cistron.

PubMed

Gäken, J; Jiang, J; Daniel, K; van Berkel, E; Hughes, C; Kuiper, M; Darling, D; Tavassoli, M; Galea-Lauri, J; Ford, K; Kemeny, M; Russell, S; Farzaneh, F

2000-12-01

Transduction of cells with multiple genes, allowing their stable and co-ordinated expression, is difficult with the available methodologies. A method has been developed for expression of multiple gene products, as fusion proteins, from a single cistron. The encoded proteins are post-synthetically cleaved and processed into each of their constituent proteins as individual, biologically active factors. Specifically, linkers encoding cleavage sites for the Golgi expressed endoprotease, furin, have been incorporated between in-frame cDNA sequences encoding different secreted or membrane bound proteins. With this strategy we have developed expression vectors encoding multiple proteins (IL-2 and B7.1, IL-4 and B7.1, IL-4 and IL-2, IL-12 p40 and p35, and IL-12 p40, p35 and IL-2 ). Transduction and analysis of over 100 individual clones, derived from murine and human tumour cell lines, demonstrate the efficient expression and biological activity of each of the encoded proteins. Fusagene vectors enable the co-ordinated expression of multiple gene products from a single, monocistronic, expression cassette.

Methods of reconstruction of multi-particle events in the new coordinate-tracking setup

NASA Astrophysics Data System (ADS)

Vorobyev, V. S.; Shutenko, V. V.; Zadeba, E. A.

2018-01-01

At the Unique Scientific Facility NEVOD (MEPhI), a large coordinate-tracking detector based on drift chambers for investigations of muon bundles generated by ultrahigh energy primary cosmic rays is being developed. One of the main characteristics of the bundle is muon multiplicity. Three methods of reconstruction of multiple events were investigated: the sequential search method, method of finding the straight line and method of histograms. The last method determines the number of tracks with the same zenith angle in the event. It is most suitable for the determination of muon multiplicity: because of a large distance to the point of generation of muons, their trajectories are quasiparallel. The paper presents results of application of three reconstruction methods to data from the experiment, and also first results of the detector operation.

Origin of Multiple Peaks in the Potentiodynamic Oxidation of CO Adlayers on Pt and Ru-Modified Pt Electrodes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Hongsen; Abruña, Héctor D.

2015-05-21

The study of the electrooxidation mechanism of COad on Pt based catalysts is very important for designing more effective CO-tolerant electrocatalysts for fuel cells. We have studied the origin of multiple peaks in the cyclic voltammograms of CO stripping from polycrystalline Pt and Ru modified polycrystalline Pt (Pt/Ru) surfaces in both acidic and alkaline media by differential electrochemical mass spectrometry (DEMS), DFT calculations, and kinetic Monte Carlo (KMC) simulations. A new COad electrooxidation kinetic model on heterogeneous Pt and Pt/Ru catalysts is proposed to account for the multiple peaks experimentally observed. In this model, OH species prefer to adsorb atmore » low-coordination sites or Ru sites and, thus, suppress CO repopulation from high-coordination sites onto these sites. Therefore, COad oxidation occurs on different facets or regions, leading to multiplicity of CO stripping peaks. This work provides a new insight into the CO electrooxidation mechanism and kinetics on heterogeneous catalysts.« less

Image-based tracking and sensor resource management for UAVs in an urban environment

NASA Astrophysics Data System (ADS)

Samant, Ashwin; Chang, K. C.

2010-04-01

Coordination and deployment of multiple unmanned air vehicles (UAVs) requires a lot of human resources in order to carry out a successful mission. The complexity of such a surveillance mission is significantly increased in the case of an urban environment where targets can easily escape from the UAV's field of view (FOV) due to intervening building and line-of-sight obstruction. In the proposed methodology, we focus on the control and coordination of multiple UAVs having gimbaled video sensor onboard for tracking multiple targets in an urban environment. We developed optimal path planning algorithms with emphasis on dynamic target prioritizations and persistent target updates. The command center is responsible for target prioritization and autonomous control of multiple UAVs, enabling a single operator to monitor and control a team of UAVs from a remote location. The results are obtained using extensive 3D simulations in Google Earth using Tangent plus Lyapunov vector field guidance for target tracking.

[The role of neurotrophic factors in regeneration of the nervous system].

PubMed

Machaliński, Bogusław; Lażewski-Banaszak, Piotr; Dąbkowska, Elżbieta; Paczkowska, Edyta; Gołąb-Janowska, Monika; Nowacki, Przemysław

2012-01-01

Neurotrophic factors regulate survival, development, and function of nervous tissue. They act via two different classes of receptors and activation of various signaling pathways in the target cells. Illumination of their physiological role in the maintenance of central nervous system homeostasis as well as regeneration of damaged tissue have ignited expectations to heal neurodegenerative diseases, including amyotrophic late-ral sclerosis and Parkinson disease. Advances in pharmaco-therapy, gene therapy, and stem cell biology have enabled development of novel therapies with application of regenerating cell transplantation. In the foreseeable future, it may lead to the establishment of safe and effective ways of treatment of these severe and currently incurable diseases.

New insight in expression, transport, and secretion of brain-derived neurotrophic factor: Implications in brain-related diseases

PubMed Central

Adachi, Naoki; Numakawa, Tadahiro; Richards, Misty; Nakajima, Shingo; Kunugi, Hiroshi

2014-01-01

Brain-derived neurotrophic factor (BDNF) attracts increasing attention from both research and clinical fields because of its important functions in the central nervous system. An adequate amount of BDNF is critical to develop and maintain normal neuronal circuits in the brain. Given that loss of BDNF function has been reported in the brains of patients with neurodegenerative or psychiatric diseases, understanding basic properties of BDNF and associated intracellular processes is imperative. In this review, we revisit the gene structure, transcription, translation, transport and secretion mechanisms of BDNF. We also introduce implications of BDNF in several brain-related diseases including Alzheimer’s disease, Huntington’s disease, depression and schizophrenia. PMID:25426265

Angels and demons: neurotrophic factors and epilepsy.

PubMed

Simonato, Michele; Tongiorgi, Enrico; Kokaia, Merab

2006-12-01

Several lines of evidence indicate that neurotrophic factors (NTFs) could be key causal mediators in the development of acquired epileptic syndromes. Yet the trophic properties of NTFs indicate that they might be used to treat epilepsy-associated damage. Accordingly, different NTFs, or even the same NTF, could produce functionally contrasting effects in the context of epilepsy. Recent experimental evidence begins to shed light on the mechanisms underlying these contrasting effects. Understanding these mechanisms will be instrumental for the development of effective therapies, which must be based on a careful consideration of the biological properties of NTFs. Here, we critically evaluate new information emerging in this area and discuss its implications for clinical treatment.

Coupling an aVLSI neuromorphic vision chip to a neurotrophic model of synaptic plasticity: the development of topography.

PubMed

Elliott, Terry; Kramer, Jörg

2002-10-01

We couple a previously studied, biologically inspired neurotrophic model of activity-dependent competitive synaptic plasticity and neuronal development to a neuromorphic retina chip. Using this system, we examine the development and refinement of a topographic mapping between an array of afferent neurons (the retinal ganglion cells) and an array of target neurons. We find that the plasticity model can indeed drive topographic refinement in the presence of afferent activity patterns generated by a real-world device. We examine the resilience of the developing system to the presence of high levels of noise by adjusting the spontaneous firing rate of the silicon neurons.

Alterations of Growth Factors in Autism and Attention-Deficit/Hyperactivity Disorder

PubMed Central

Galvez-Contreras, Alma Y.; Campos-Ordonez, Tania; Gonzalez-Castaneda, Rocio E.; Gonzalez-Perez, Oscar

2017-01-01

Growth factors (GFs) are cytokines that regulate the neural development. Recent evidence indicates that alterations in the expression level of GFs during embryogenesis are linked to the pathophysiology and clinical manifestations of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASD). In this concise review, we summarize the current evidence that supports the role of brain-derived neurotrophic factor, insulin-like growth factor 2, hepatocyte growth factor (HGF), glial-derived neurotrophic factor, nerve growth factor, neurotrophins 3 and 4, and epidermal growth factor in the pathogenesis of ADHD and ASD. We also highlight the potential use of these GFs as clinical markers for diagnosis and prognosis of these neurodevelopmental disorders. PMID:28751869

Solution Concepts for Distributed Decision-Making without Coordination

NASA Technical Reports Server (NTRS)

Beling, Peter A.; Patek, Stephen D.

2005-01-01

Consider a single-stage problem in which we have a group N agents who are attempting to minimize the expected cost of their joint actions, without the benefit of communication or a pre-established protocol but with complete knowledge of the expected cost of any joint set of actions for the group. We call this situation a static coordination problem. The central issue in defining an appropriate solution concept for static coordination problems is considering how to deal with the fact that if the agents axe faced with a set of multiple (mixed) strategies that are equally attractive in terms of cost, a failure of coordination may lead to an expected cost value that is worse than that of any of the strategies in the set. In this proposal, we describe the notion of a general coordination problem, describe initial efforts at developing a solution concept for static coordination problems, and then outline a research agenda that centers on activities that will be basis for obtaining a complete understanding of solutions to static coordination problems.

Streamlining Collaborative Planning in Spacecraft Mission Architectures

NASA Technical Reports Server (NTRS)

Misra, Dhariti; Bopf, Michel; Fishman, Mark; Jones, Jeremy; Kerbel, Uri; Pell, Vince

2000-01-01

During the past two decades, the planning and scheduling community has substantially increased the capability and efficiency of individual planning and scheduling systems. Relatively recently, research work to streamline collaboration between planning systems is gaining attention. Spacecraft missions stand to benefit substantially from this work as they require the coordination of multiple planning organizations and planning systems. Up to the present time this coordination has demanded a great deal of human intervention and/or extensive custom software development efforts. This problem will become acute with increased requirements for cross-mission plan coordination and multi -spacecraft mission planning. The Advanced Architectures and Automation Branch of NASA's Goddard Space Flight Center is taking innovative steps to define collaborative planning architectures, and to identify coordinated planning tools for Cross-Mission Campaigns. Prototypes are being developed to validate these architectures and assess the usefulness of the coordination tools by the planning community. This presentation will focus on one such planning coordination too], named Visual Observation Layout Tool (VOLT), which is currently being developed to streamline the coordination between astronomical missions

[Raman spectroscopic study of binary PbO-TeO2 glasses].

PubMed

Huang, Li; You, Jing-Lin; Chen, Hui; Jiang, Guo-Chang

2008-07-01

Raman spectra of lead tellurite glasses and their melts were measured. Results show that four coordinate tellurite units convert into three coordinate units with increasing the concentration of PbO, and the number of non-bridging oxygen bonds (NBO) increases accordingly in this system. Three spectral peaks in the high frequency range were assigned to stretching vibration of bridging oxygen in four coordinate tellurite units (Q(b)), stretching vibration of non-bridging oxygen in four coordinate tellurite units (Q(nb)) and in three coordinate tellurite units (T(nb)). The relative density of four coordinate structure units decreases and the three coordinate tellurite units considerably exist in tellurite glasses when the concentration of PbO > 50%. Besides, the Raman frequencies of the three species' peaks become blue-shifted because of the temperature induced crystallization at high temperature, and the peak intensities increase and the peaks sharpen. The peaks merge together and become much broader while the glass is heated above the melting point because of multiple microstructure units coexisting.

Understanding the occupational and organizational boundaries to safe hospital discharge.

PubMed

Waring, Justin; Marshall, Fiona; Bishop, Simon

2015-01-01

Safe hospital discharge relies upon communication and coordination across multiple occupational and organizational boundaries. Our aim was to understand how these boundaries can exacerbate health system complexity and represent latent sociocultural threats to safe discharge. An ethnographic study was conducted in two local health and social care systems (health economies) in England, focusing on two clinical areas: stroke and hip fracture patients. Data collection involved 345 hours of observations and 220 semi-structured interviews with health and social care professionals, patients and their lay carers. Hospital discharge involves a dynamic network of interactions between heterogeneous health and social care actors, each characterized by divergent ways of organizing discharge activities; cultures of collaboration and interaction and understanding of what discharge involves and how it contributes to patient recovery. These interrelated dimensions elaborate the occupational and organisational boundaries that can influence communication and coordination in hospital discharge. Hospital discharge relies upon the coordination of multiple actors working across occupational and organizational boundaries. Attention to the sociocultural boundaries that influence communication and coordination can help inform interventions that might support enhanced discharge safety. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Simultaneous Helmert transformations among multiple frames considering all relevant measurements

NASA Astrophysics Data System (ADS)

Chang, Guobin; Lin, Peng; Bian, Hefang; Gao, Jingxiang

2018-03-01

Helmert or similarity models are widely employed to relate different coordinate frames. It is often encountered in practice to transform coordinates from more than one old frame into a new one. One may perform separate Helmert transformations for each old frame. However, although each transformation is locally optimal, this is not globally optimal. Transformations among three frames, namely one new and two old, are studied as an example. Simultaneous Helmert transformations among all frames are also studied. Least-squares estimation of the transformation parameters and the coordinates in the new frame of all stations involved is performed. A functional model for the transformations among multiple frames is developed. A realistic stochastic model is followed, in which not only non-common stations are taken into consideration, but also errors in all measurements are addressed. An algorithm of iterative linearizations and estimations is derived in detail. The proposed method is globally optimal, and, perhaps more importantly, it produces a unified network of the new frame providing coordinate estimates for all involved stations and the associated covariance matrix, with the latter being consistent with the true errors of the former. Simulations are conducted, and the results validate the superiority of the proposed combined method over separate approaches.

Neural basis for hand muscle synergies in the primate spinal cord.

PubMed

Takei, Tomohiko; Confais, Joachim; Tomatsu, Saeka; Oya, Tomomichi; Seki, Kazuhiko

2017-08-08

Grasping is a highly complex movement that requires the coordination of multiple hand joints and muscles. Muscle synergies have been proposed to be the functional building blocks that coordinate such complex motor behaviors, but little is known about how they are implemented in the central nervous system. Here we demonstrate that premotor interneurons (PreM-INs) in the primate cervical spinal cord underlie the spatiotemporal patterns of hand muscle synergies during a voluntary grasping task. Using spike-triggered averaging of hand muscle activity, we found that the muscle fields of PreM-INs were not uniformly distributed across hand muscles but rather distributed as clusters corresponding to muscle synergies. Moreover, although individual PreM-INs have divergent activation patterns, the population activity of PreM-INs reflects the temporal activation of muscle synergies. These findings demonstrate that spinal PreM-INs underlie the muscle coordination required for voluntary hand movements in primates. Given the evolution of neural control of primate hand functions, we suggest that spinal premotor circuits provide the fundamental coordination of multiple joints and muscles upon which more fractionated control is achieved by superimposed, phylogenetically newer, pathways.

Shared periodic performer movements coordinate interactions in duo improvisations.

PubMed

Eerola, Tuomas; Jakubowski, Kelly; Moran, Nikki; Keller, Peter E; Clayton, Martin

2018-02-01

Human interaction involves the exchange of temporally coordinated, multimodal cues. Our work focused on interaction in the visual domain, using music performance as a case for analysis due to its temporally diverse and hierarchical structures. We made use of two improvising duo datasets-(i) performances of a jazz standard with a regular pulse and (ii) non-pulsed, free improvizations-to investigate whether human judgements of moments of interaction between co-performers are influenced by body movement coordination at multiple timescales. Bouts of interaction in the performances were manually annotated by experts and the performers' movements were quantified using computer vision techniques. The annotated interaction bouts were then predicted using several quantitative movement and audio features. Over 80% of the interaction bouts were successfully predicted by a broadband measure of the energy of the cross-wavelet transform of the co-performers' movements in non-pulsed duos. A more complex model, with multiple predictors that captured more specific, interacting features of the movements, was needed to explain a significant amount of variance in the pulsed duos. The methods developed here have key implications for future work on measuring visual coordination in musical ensemble performances, and can be easily adapted to other musical contexts, ensemble types and traditions.

Infrared Multiple-Photon Dissociation spectroscopy of group II metal complexes with salicylate

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ryan P. Dain; Gary Gresham; Gary S. Groenewold

2011-07-01

Ion-trap tandem mass spectrometry with collision-induced dissociation, and the combination of infrared multiple-photon dissociation (IRMPD) spectroscopy and density functional theory (DFT) calculations were used to characterize singly-charged, 1:1 complexes of Ca2+, Sr2+ and Ba2+ with salicylate. For each metal-salicylate complex, the CID pathways are: (a) elimination of CO2 and (b) formation of [MOH]+ where M=Ca2+, Sr2+ or Ba2+. DFT calculations predict three minima for the cation-salicylate complexes which differ in the mode of metal binding. In the first, the metal ion is coordinated by O atoms of the (neutral) phenol and carboxylate groups of salicylate. In the second, the cationmore » is coordinated by phenoxide and (neutral) carboxylic acid groups. The third mode involves coordination by the carboxylate group alone. The infrared spectrum for the metal-salicylate complexes contains a number of absorptions between 1000 – 1650 cm-1, and the best correlation between theoretical and experimental spectra for the structure that features coordination of the metal ion by phenoxide and the carbonyl group of the carboxylic acid group, consistent with calculated energies for the respective species.« less

Infrared multiple-photon dissociation spectroscopy of group II metal complexes with salicylate.

PubMed

Dain, Ryan P; Gresham, Gary; Groenewold, Gary S; Steill, Jeffrey D; Oomens, Jos; van Stipdonk, Michael J

2011-07-15

Ion trap tandem mass spectrometry with collision-induced dissociation, and the combination of infrared multiple-photon dissociation (IRMPD) spectroscopy and density functional theory (DFT) calculations, were used to characterize singly charged, 1:1 complexes of Ca(2+), Sr(2+) and Ba(2+) with salicylate. For each metal-salicylate complex, the CID pathways are: (a) elimination of CO(2) and (b) formation of [MOH](+) where M = Ca(2+), Sr(2+) or Ba(2+). DFT calculations predict three minima for the cation-salicylate complexes which differ in the mode of metal binding. In the first, the metal ion is coordinated by O atoms of the (neutral) phenol and carboxylate groups of salicylate. In the second, the cation is coordinated by phenoxide and (neutral) carboxylic acid groups. The third mode involves coordination by the carboxylate group alone. The infrared spectrum for the metal-salicylate complexes contains a number of absorptions between 1000 and 1650 cm(-1), and the best correlation between theoretical and experimental spectra is found for the structure that features coordination of the metal ion by phenoxide and the carbonyl O of the carboxylic acid group, consistent with the calculated energies for the respective species. Copyright © 2011 John Wiley & Sons, Ltd.

N-(sulfoethyl) iminodiacetic acid-based lanthanide coordination polymers: Synthesis, magnetism and quantum Monte Carlo studies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhuang Guilin, E-mail: glzhuang@zjut.edu.cn; Chen Wulin; Zheng Jun

2012-08-15

A series of lanthanide coordination polymers have been obtained through the hydrothermal reaction of N-(sulfoethyl) iminodiacetic acid (H{sub 3}SIDA) and Ln(NO{sub 3}){sub 3} (Ln=La, 1; Pr, 2; Nd, 3; Gd, 4). Crystal structure analysis exhibits that lanthanide ions affect the coordination number, bond length and dimension of compounds 1-4, which reveal that their structure diversity can be attributed to the effect of lanthanide contraction. Furthermore, the combination of magnetic measure with quantum Monte Carlo(QMC) studies exhibits that the coupling parameters between two adjacent Gd{sup 3+} ions for anti-anti and syn-anti carboxylate bridges are -1.0 Multiplication-Sign 10{sup -3} and -5.0 Multiplication-Signmore » 10{sup -3} cm{sup -1}, respectively, which reveals weak antiferromagnetic interaction in 4. - Graphical abstract: Four lanthanide coordination polymers with N-(sulfoethyl) iminodiacetic acid were obtained under hydrothermal condition and reveal the weak antiferromagnetic coupling between two Gd{sup 3+} ions by Quantum Monte Carlo studies. Highlights: Black-Right-Pointing-Pointer Four lanthanide coordination polymers of H{sub 3}SIDA ligand were obtained. Black-Right-Pointing-Pointer Lanthanide ions play an important role in their structural diversity. Black-Right-Pointing-Pointer Magnetic measure exhibits that compound 4 features antiferromagnetic property. Black-Right-Pointing-Pointer Quantum Monte Carlo studies reveal the coupling parameters of two Gd{sup 3+} ions.« less

Achievements and barriers in the organ donation process: a critical analysis of donation coordinators' discourse.

PubMed

Mercado-Martínez, Francisco J; Díaz-Medina, Blanca A; Hernández-Ibarra, Eduardo

2013-09-01

Donation coordinators play an important role in the success or failure of organ donation and transplant programs. Nevertheless, these professionals' perspectives and practices have hardly been explored, particularly in low- and middle-income countries. To examine donation coordinators' discourse on the organ donation process and the barriers they perceive. A critical qualitative study was carried out in Guadalajara, Mexico. Twelve donation coordinators from public and private hospitals participated. DATA GATHERING AND ANALYSIS: Data were gathered by using semistructured interviews and critical discourse analysis. Participants indicated that partial results have been achieved in deceased organ donation. Concomitantly, multiple obstacles have adversely affected the process and outcomes: at the structural level, the fragmentation of the health system and the scarcity of financial and material resources; at the relational level, nonegalitarian relationships between coordinators and hospital personnel; at the ideational level, the transplant domain and its specialists overshadow the donation domain and its coordinators. Negative images are associated with donation coordinators. Organ donation faces structural, relational, and ideational barriers; hence, complex interventions should be undertaken. Donation coordinators also should be recognized by the health system.

Neurotrophin receptor structure and interactions.

PubMed

Yano, H; Chao, M V

2000-03-01

Although ligand-induced dimerization or oligomerization of receptors is a well established mechanism of growth factor signaling, increasing evidence indicates that biological responses are often mediated by receptor trans-signaling mechanisms involving two or more receptor systems. These include G protein-coupled receptors, cytokine, growth factor and trophic factor receptors. Greater flexibility is provided when different signaling pathways are merged through multiple receptor signaling systems. Trophic factors exemplified by NGF and its family members, ciliary neurotrophic factor (CNTF) and glial derived neurotrophic factor (GDNF) all utilize increased tyrosine phosphorylation of cellular substrates to mediate neuronal cell survival. Actions of the NGF family of neurotrophins are not only dictated by ras activation through the Trk family of receptor tyrosine kinases, but also a survival pathway defined by phosphatidylinositol-3-kinase activity (Yao and Cooper, 1995), which gives rise to phosphoinositide intermediates that activate the serine/threonine kinase Akt/PKB (Dudek et al., 1997). Induction of the serine-threonine kinase activity is critical for cell survival, as well as cell proliferation. Hence, for many trophic factors, multiple proteins constitute a functional multisubunit receptor complex that activates ras-dependent and ras-independent intracellular signaling. The NGF receptors provide an example of bidirectional crosstalk. In the presence of TrkA receptors, p75 can participate in the formation of high affinity binding sites and enhanced neurotrophin responsiveness leading to a survival or differentiation signal. In the absence of TrkA receptors, p75 can generate, in only specific cell populations, a death signal. These activities include the induction of NF kappa B (Carter et al., 1996); the hydrolysis of sphingomyelin to ceramide (Dobrowsky et al., 1995); and the pro-apoptotic functions attributed to p75. Receptors are generally drawn and viewed as isolated integral membrane proteins which span the lipid bilayer, with signal transduction proceeding in a linear step-wise fashion. There are now numerous examples which indicate that each receptor acts not only in a linear, independent manner, but can also influence the activity of other cell surface receptors, either directly or through signaling intermediates. Which step and which intermediates are utilized for crosstalk between the receptors is a critical question. For neurotrophins, their primary function in sustaining the viability of neurons is counterbalanced by a receptor mechanism to eliminate cells by an apoptotic mechanism. It is conceivable that this bidirectional system may be utilized selectively during development and in neurodegenerative diseases.

Astrocytes produce an insulin-like neurotrophic factor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kadle, R.; Suksang, C.; Fellows, R.E.

1986-05-01

They have previously reported that survival of dissociated neurons from fetal rat telencephalon plated at low density in serum-free, hormone-free defined medium is enhanced in the presence of insulin. In the absence of insulin a similar effect on neuronal survival is observed if cells are grown in medium conditioned by glial cells. The present study was carried out to characterize the insulin-like neurotrophic activity present in the glial conditioned medium (GLCM). Conditioned medium from confluent cultures of astrogial cells maintained in a serum free defined medium without insulin was collected every two or three days. A 5 to 30kDa fractionmore » of this medium was obtained by filtering it sequentially through YM30 and YM5 membrane filters. Binding of /sup 125/I-insulin to high density neuronal cultures was inhibited 43% by this fraction. Radioimmunoassay for insulin indicated that 1-2 ng of immuno-reactive insulin were present per ml of GLCM. Immunosequestration of the factor by insulin antibodies bound to protein A agarose gel resulted in loss of neurotrophic activity of the 5 to 30 kDa fraction. These results indicate that cultured astrocytes produce a factor immunologically and biochemically similar to insulin. This factor enhances the survival of neurons in culture and may be important for their normal development and differentiation.« less

Neurotrophic effects of growth/differentiation factor 5 in a neuronal cell line.

PubMed

Toulouse, André; Collins, Grace C; Sullivan, Aideen M

2012-04-01

The neurotrophin growth/differentiation factor 5 (GDF5) is studied as a potential therapeutic agent for Parkinson's disease as it is believed to play a role in the development and maintenance of the nigrostriatal system. Progress in understanding the effects of GDF5 on dopaminergic neurones has been hindered by the use of mixed cell populations derived from primary cultures or in vivo experiments, making it difficult to differentiate between direct and indirect effects of GDF5 treatment on neurones. In an attempt to establish an useful model to study the direct neuronal influence of GDF5, we have characterised the effects of GDF5 on a human neuronal cell line, SH-SY5Y. Our results show that GDF5 has the capability to promote neuronal but not dopaminergic differentiation. We also show that it promotes neuronal survival in vitro following a 6-hydroxydopamine insult. Our results show that application of GDF5 to SH-SY5Y cultures induces the SMAD pathway which could potentially be implicated in the intracellular transmission of GDF5's neurotrophic effects. Overall, our study shows that the SH-SY5Y neuroblastoma cell line provides an excellent neuronal model to study the neurotrophic effects of GDF5.

Focused ultrasound-enhanced intranasal brain delivery of brain-derived neurotrophic factor

NASA Astrophysics Data System (ADS)

Chen, Hong; Yang, Georgiana Zong Xin; Getachew, Hoheteberhan; Acosta, Camilo; Sierra Sánchez, Carlos; Konofagou, Elisa E.

2016-06-01

The objective of this study was to unveil the potential mechanism of focused ultrasound (FUS)-enhanced intranasal (IN) brain drug delivery and assess its feasibility in the delivery of therapeutic molecules. Delivery outcomes of fluorescently-labeled dextrans to mouse brains by IN administration either before or after FUS sonication were compared to evaluate whether FUS enhances IN delivery by active pumping or passive diffusion. Fluorescence imaging of brain slices found that IN administration followed by FUS sonication achieved significantly higher delivery than IN administration only, while pre-treatment by FUS sonication followed by IN administration was not significantly different from IN administration only. Brain-derived neurotrophic factor (BDNF), a promising neurotrophic factor for the treatment of many central nervous system diseases, was delivered by IN followed by FUS to demonstrate the feasibility of this technique and compared with the established FUS technique where drugs are injected intravenously. Immunohistochemistry staining of BDNF revealed that FUS-enhanced IN delivery achieved similar locally enhanced delivery as the established FUS technique. This study suggested that FUS enhances IN brain drug delivery by FUS-induced active pumping of the drug and demonstrated that FUS-enhanced IN delivery is a promising technique for noninvasive and localized delivery of therapeutic molecules to the brain.

IGF-1 and BDNF promote chick bulbospinal neurite outgrowth in vitro.

PubMed

Salie, Rishard; Steeves, John D

2005-11-01

Injured neurons in the CNS do not experience significant functional regeneration and so spinal cord insult often results in permanently compromised locomotor ability. The capability of a severed axon to re-grow is thought to depend on numerous factors, one of which is the decreased availability of neurotrophic factors. Application of trophic factors to axotomized neurons has been shown to enhance survival and neurite outgrowth. Although brainstem-spinal connections play a pivotal role in motor dysfunction after spinal cord injury, relatively little is known about the trophic sensitivity of these populations. This study explores the response of bulbospinal populations to various trophic factors. Several growth factors were initially examined for potential trophic effects on the projection neurons of the brainstem. Brain derived neurotrophic factor (BDNF) and insulin-like growth factor (IGF-1) significantly enhance mean process length in both the vestibulospinal neurons and spinal projection neurons from the raphe nuclei. Nerve growth factor (NGF), neurotrophin-4 (NT-4) and glial derived neurotrophic factor (GDNF) did not effect process outgrowth in vestibulospinal neurons. At the developmental stages used in this study, it was determined that receptors for BDNF and IGF-1 were present both on bulbospinal neurons and on surrounding cells with a non-neuronal morphology.

Glial Cell Line-Derived Neurotrophic Factor (GDNF) serum level in women with schizophrenia and depression, correlation with clinical and metabolic parameters.

PubMed

Skibinska, Maria; Kapelski, Pawel; Pawlak, Joanna; Rajewska-Rager, Aleksandra; Dmitrzak-Weglarz, Monika; Szczepankiewicz, Aleksandra; Czerski, Piotr; Twarowska-Hauser, Joanna

2017-10-01

Neurotrophic factors have been implicated in neuropsychiatric disorders, including schizophrenia and depression. Glial Cell Line-Derived Neurotrophic Factor (GDNF) promotes development, differentiation, and protection of dopaminergic, serotonergic, GABAergic and noradrenergic neurons as well as glial cells in different brain regions. This study examined serum levels of GDNF in schizophrenia and depression and its correlation with metabolic parameters during 8 weeks of treatment. Serum GDNF level, fasting serum glucose and lipid profile were measured at baseline and week 8 in 133 women: 55 with schizophrenia, 30 with a first episode depression and 48 healthy controls. The severity of the symptoms was evaluated using Positive and Negative Syndrome Scale (PANSS), 17-item Hamilton Depression Rating Scale (HDRS) and Beck Depression Inventory (BDI). There was statistically significant higher GDNF level in schizophrenia at baseline when compared with week 8. Correlations of GDNF with PANSS in schizophrenia and cholesterol level in depression have also been detected. To our knowledge, this is the first study which correlates GDNF levels with metabolic parameters. Our results show no differences in GDNF serum level between schizophrenia, a first depressive episode, and healthy controls. GDNF serum level did not correlate with metabolic parameters except for total cholesterol in depression. Copyright © 2017 Elsevier B.V. All rights reserved.

Influence of Delivery Method on Neuroprotection by Bone Marrow Mononuclear Cell Therapy following Ventral Root Reimplantation with Fibrin Sealant

PubMed Central

Barbizan, Roberta; Castro, Mateus V.; Barraviera, Benedito; Ferreira, Rui S.; Oliveira, Alexandre L. R.

2014-01-01

The present work compared the local injection of mononuclear cells to the spinal cord lateral funiculus with the alternative approach of local delivery with fibrin sealant after ventral root avulsion (VRA) and reimplantation. For that, female adult Lewis rats were divided into the following groups: avulsion only, reimplantation with fibrin sealant; root repair with fibrin sealant associated with mononuclear cells; and repair with fibrin sealant and injected mononuclear cells. Cell therapy resulted in greater survival of spinal motoneurons up to four weeks post-surgery, especially when mononuclear cells were added to the fibrin glue. Injection of mononuclear cells to the lateral funiculus yield similar results to the reimplantation alone. Additionally, mononuclear cells added to the fibrin glue increased neurotrophic factor gene transcript levels in the spinal cord ventral horn. Regarding the motor recovery, evaluated by the functional peroneal index, as well as the paw print pressure, cell treated rats performed equally well as compared to reimplanted only animals, and significantly better than the avulsion only subjects. The results herein demonstrate that mononuclear cells therapy is neuroprotective by increasing levels of brain derived neurotrophic factor (BDNF) and glial derived neurotrophic factor (GDNF). Moreover, the use of fibrin sealant mononuclear cells delivery approach gave the best and more long lasting results. PMID:25157845

A putative model of overeating and obesity based on brain-derived neurotrophic factor: direct and indirect effects.

PubMed

Ooi, Cara L; Kennedy, James L; Levitan, Robert D

2012-08-01

Increased food intake is a major contributor to the obesity epidemic in all age groups. Elucidating brain systems that drive overeating and that might serve as targets for novel prevention and treatment interventions is thus a high priority for obesity research. The authors consider 2 major pathways by which decreased activity of brain-derived neurotrophic factor (BDNF) may confer vulnerability to overeating and weight gain in an obesogenic environment. The first "direct" pathway focuses on the specific role of BDNF as a mediator of food intake control at brain areas rich in BDNF receptors, including the hypothalamus and hindbrain. It is proposed that low BDNF activity limited to this direct pathway may best explain overeating and obesity outside the context of major neuropsychiatric disturbance. A second "indirect" pathway considers the broad neurotrophic effects of BDNF on key monoamine systems that mediate mood dysregulation, impulsivity, and executive dysfunction as well as feeding behavior per se. Disruption in this pathway may best explain overeating and obesity in the context of various neuropsychiatric disturbances including mood disorders, attention-deficit disorder, and/or binge eating disorders. An integrative model that considers these potential roles of BDNF in promoting obesity is presented. The implications of this model for the early prevention and treatment of obesity are also considered.

Role of brain-derived neurotrophic factor during the regenerative response after traumatic brain injury in adult zebrafish.

PubMed

Cacialli, Pietro; Palladino, Antonio; Lucini, Carla

2018-06-01

Several mammalian animal models of traumatic brain injury have been used, mostly rodents. However, reparative mechanisms in mammalian brain are very limited, and newly formed neurons do not survive for long time. The brain of adult zebrafish, a teleost fish widely used as vertebrate model, possesses high regenerative properties after injury due to the presence of numerous stem cells niches. The ventricular lining of the zebrafish dorsal telencephalon is the most studied neuronal stem cell niche because its dorso-lateral zone is considered the equivalent to the hippocampus of mammals which contains one of the two constitutive neurogenic niches of mammals. To mimic TBI, stab wound in the dorso-lateral telencephalon of zebrafish was used in studies devoted to fish regenerative properties. Brain-derived neurotrophic factor, which is known to play key roles in the repair process after traumatic brain lesions, persists around the lesioned area of injured telencephalon of adult zebrafish. These results are extensively compared to reparative processes in rodent brain. Considering the complete repair of the damaged area in fish, it could be tempting to consider brain-derived neurotrophic factor as a factor contributing to create a permissive environment that enables the establishment of new neuronal population in damaged brain.

Synergistic Effects of GDNF and VEGF on Lifespan and Disease Progression in a Familial ALS Rat Model

PubMed Central

Krakora, Dan; Mulcrone, Patrick; Meyer, Michael; Lewis, Christina; Bernau, Ksenija; Gowing, Genevieve; Zimprich, Chad; Aebischer, Patrick; Svendsen, Clive N; Suzuki, Masatoshi

2013-01-01

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons in the brain and spinal cord. We have recently shown that human mesenchymal stem cells (hMSCs) modified to release glial cell line-derived neurotrophic factor (GDNF) decrease disease progression in a rat model of ALS when delivered to skeletal muscle. In the current study, we determined whether or not this effect could be enhanced by delivering GDNF in concert with other trophic factors. hMSC engineered to secrete GDNF (hMSC-GDNF), vascular endothelial growth factor (hMSC-VEGF), insulin-like growth factor-I (hMSC-IGF-I), or brain-derived neurotrophic factor (hMSC-BDNF), were prepared and transplanted bilaterally into three muscle groups. hMSC-GDNF and hMSC-VEGF prolonged survival and slowed the loss of motor function, but hMSC-IGF-I and hMSC-BDNF did not have any effect. We then tested the efficacy of a combined ex vivo delivery of GDNF and VEGF in extending survival and protecting neuromuscular junctions (NMJs) and motor neurons. Interestingly, the combined delivery of these neurotrophic factors showed a strong synergistic effect. These studies further support ex vivo gene therapy approaches for ALS that target skeletal muscle. PMID:23712039

Using minimalist self-assembling peptides as hierarchical scaffolds to stabilise growth factors and promote stem cell integration in the injured brain.

PubMed

Rodriguez, A L; Bruggeman, K F; Wang, Y; Wang, T Y; Williams, R J; Parish, C L; Nisbet, D R

2018-03-01

Neurotrophic growth factors are effective in slowing progressive degeneration and/or promoting neural repair through the support of residual host and/or transplanted neurons. However, limitations including short half-life and enzyme susceptibility of growth factors highlight the need for alternative strategies to prolong localised delivery at a site of injury. Here, we establish the utility of minimalist N-fluorenylmethyloxycarbonyl (Fmoc) self-assembling peptides (SAPs) as growth factor delivery vehicle, targeted at supporting neural transplants in an animal model of Parkinson's disease. The neural tissue-specific SAP, Fmoc-DIKVAV, demonstrated sustained release of glial cell line derived neurotrophic factor, up to 172 hr after gel loading. This represents a significant advance in drug delivery, because its lifetime in phosphate buffered saline was less than 1 hr. In vivo transplantation of neural progenitor cells, together with our growth factor-loaded material, into the injured brain improved graft survival compared with cell transplants alone. We show for the first time the use of minimalist Fmoc-SAP in an in vivo disease model for sustaining the delivery of neurotrophic growth factors, facilitating their spatial and temporal delivery in vivo, whilst also providing an enhanced niche environment for transplanted cells. Copyright © 2017 John Wiley & Sons, Ltd.

Neurotrophic factor - Characterization and partial purification

NASA Technical Reports Server (NTRS)

Popiela, H.; Ellis, S.

1981-01-01

Recent evidence suggests that neurotrophic activity is required for the normal proliferation and development of muscle cells. The present paper reports a study of the purification and characterization of a neurotrophic factor (NTF) from adult chicken ischiatic-peroneal nerves using two independent quantitative in vitro assay systems. The assays were performed by the measurement of the incorporation of tritiated thymidine or the sizes of single-cell clones by chick muscle cells grown in culture. The greatest amount of neutrotrophic activity is found to be extracted at a pH of 8; aqueous suspensions of the activity are stable to long-term storage at room temperature. The specific activity of the substance is doubled upon precipitation with ammonium sulfate or after gel filtration, and increase 4 to 5 fold after salt gradient elution from DEAE cellulose columns. The active fraction obtained after gel filtration and rechromatography on DEAE cellulose exhibits a 7 to 10-fold increase in specific activity. Electrophoresis of the most highly purified material yields a greatly concentrated band at around 80,000 daltons. Although NTF is purified almost 10-fold as indicated by the increase in specific activity, the maximum activity of the partially purified material is greatly reduced, possibly due to a requirement for a cofactor for the expression of maximum activity.

Correlation between three color coordinates of human teeth.

PubMed

Lee, Yong-Keun

2014-11-01

The objective was to determine whether there were significant correlations in the three color coordinates within each of two color coordinate systems, such as the Commission Internationale de l’Eclairage (CIE) L*a*b* system, and the lightness, chroma, and hue angle system, of human vital teeth. The color of six maxillary and six mandibular anterior teeth was measured by the Shade Vision System. Pearson correlations between each pair of the color coordinates were determined (α=0.01 ). The influence of two color coordinates on the other color coordinate was determined with a multiple regression analysis (α=0.01 ). Based on correlation analyses, all the color coordinate pairs showed significant correlations except for the chroma and hue angle pair. The CIE L* was negatively correlated with the CIE a*,b*, and chroma, but positively correlated with the hue angle. The CIE a* was positively correlated with the CIE b* and chroma. Tooth color coordinates were correlated each other. Lighter teeth were less chromatic both in the CIE a* and b* coordinates. Therefore, it was postulated that the three color coordinates of human teeth were harmonized within certain color attribute ranges, and a lack of correlations in these coordinates might indicate external/internal discolorations and/or anomalies of teeth.

Correlation between three color coordinates of human teeth

NASA Astrophysics Data System (ADS)

Lee, Yong-Keun

2014-11-01

The objective was to determine whether there were significant correlations in the three color coordinates within each of two color coordinate systems, such as the Commission Internationale de l'Eclairage (CIE) L*a*b* system, and the lightness, chroma, and hue angle system, of human vital teeth. The color of six maxillary and six mandibular anterior teeth was measured by the Shade Vision System. Pearson correlations between each pair of the color coordinates were determined (α=0.01). The influence of two color coordinates on the other color coordinate was determined with a multiple regression analysis (α=0.01). Based on correlation analyses, all the color coordinate pairs showed significant correlations except for the chroma and hue angle pair. The CIE L* was negatively correlated with the CIE a*, b*, and chroma, but positively correlated with the hue angle. The CIE a* was positively correlated with the CIE b* and chroma. Tooth color coordinates were correlated each other. Lighter teeth were less chromatic both in the CIE a* and b* coordinates. Therefore, it was postulated that the three color coordinates of human teeth were harmonized within certain color attribute ranges, and a lack of correlations in these coordinates might indicate external/internal discolorations and/or anomalies of teeth.

Brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT3) levels in post-mortem brain tissue from patients with depression compared to healthy individuals - a proof of concept study.

PubMed

Sheldrick, A; Camara, S; Ilieva, M; Riederer, P; Michel, T M

2017-10-01

The neurotrophic factors (NTF) hypothesis of depression was postulated nearly a decade ago and is nowadays widely acknowledged. Previous reports suggest that cerebral concentrations of NTF may be reduced in suicide victims who received minimal or no antidepressant pharmacotherapy. Recent evidence suggests that antidepressant treatment may improve or normalise cerebral concentrations of neurotrophic factors. Therefore, we examined the concentration of brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT3) in different brain regions (cortex, cingulate gyrus, thalamus, hippocampus, putamen and nucleus caudatus) of 21 individuals - 7 patients of which 4 patients with major depressive disorder (MDD) and overall age 86.8±5 years who received antidepressant pharmacotherapy (selective serotonin re-uptake inhibitors [SSRI]; tricyclic antidepressants [TCA]), 3 patients with MDD without antidepressant treatment and overall age 84.3±5 years versus 14 unaffected subjects at age 70.3±13.8. We detected significant elevation of BDNF (parietal cortex) and NT3 (parietal, temporal and occipital cortex, cingulate gyrus, thalamus, putamen and nucleus caudatus regions) in MDD patients who received antidepressant medication compared to MDD untreated patients and controls. Moreover, we detected a significant decrease of NT3 levels in the parietal cortex of patients suffering from MDD non-treated patients without treatment compared to healthy individuals. Although the limited statistical power due to the small sample size in this proof of concept study corroborates data from previous studies, which show that treatment with antidepressants mediates alterations in neuroplasticity via the action of NTF. However, more research using post-mortem brain tissue with larger samples needs to be carried out as well as longitudinal studies to further verify these results. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Posttraumatic Propofol Neurotoxicity Is Mediated via the Pro-Brain-Derived Neurotrophic Factor-p75 Neurotrophin Receptor Pathway in Adult Mice.

PubMed

Sebastiani, Anne; Granold, Matthias; Ditter, Anja; Sebastiani, Philipp; Gölz, Christina; Pöttker, Bruno; Luh, Clara; Schaible, Eva-Verena; Radyushkin, Konstantin; Timaru-Kast, Ralph; Werner, Christian; Schäfer, Michael K; Engelhard, Kristin; Moosmann, Bernd; Thal, Serge C

2016-02-01

The gamma-aminobutyric acid modulator propofol induces neuronal cell death in healthy immature brains by unbalancing neurotrophin homeostasis via p75 neurotrophin receptor signaling. In adulthood, p75 neurotrophin receptor becomes down-regulated and propofol loses its neurotoxic effect. However, acute brain lesions, such as traumatic brain injury, reactivate developmental-like programs and increase p75 neurotrophin receptor expression, probably to foster reparative processes, which in turn could render the brain sensitive to propofol-mediated neurotoxicity. This study investigates the influence of delayed single-bolus propofol applications at the peak of p75 neurotrophin receptor expression after experimental traumatic brain injury in adult mice. Randomized laboratory animal study. University research laboratory. Adult C57BL/6N and nerve growth factor receptor-deficient mice. Sedation by IV propofol bolus application delayed after controlled cortical impact injury. Propofol sedation at 24 hours after traumatic brain injury increased lesion volume, enhanced calpain-induced αII-spectrin cleavage, and increased cell death in perilesional tissue. Thirty-day postinjury motor function determined by CatWalk (Noldus Information Technology, Wageningen, The Netherlands) gait analysis was significantly impaired in propofol-sedated animals. Propofol enhanced pro-brain-derived neurotrophic factor/brain-derived neurotrophic factor ratio, which aggravates p75 neurotrophin receptor-mediated cell death. Propofol toxicity was abolished both by pharmacologic inhibition of the cell death domain of the p75 neurotrophin receptor (TAT-Pep5) and in mice lacking the extracellular neurotrophin binding site of p75 neurotrophin receptor. This study provides first evidence that propofol sedation after acute brain lesions can have a deleterious impact and implicates a role for the pro-brain-derived neurotrophic factor-p75 neurotrophin receptor pathway. This observation is important as sedation with propofol and other compounds with GABA receptor activity are frequently used in patients with acute brain pathologies to facilitate sedation or surgical and interventional procedures.

BDNF-GSK-3β-β-Catenin Pathway in the mPFC Is Involved in Antidepressant-Like Effects of Morinda officinalis Oligosaccharides in Rats.

PubMed

Xu, Ling-Zhi; Xu, De-Feng; Han, Ying; Liu, Li-Jing; Sun, Cheng-Yu; Deng, Jia-Hui; Zhang, Ruo-Xi; Yuan, Ming; Zhang, Su-Zhen; Li, Zhi-Meng; Xu, Yi; Li, Jin-Sheng; Xie, Su-Hua; Li, Su-Xia; Zhang, Hong-Yan; Lu, Lin

2017-01-01

Morinda officinalis oligosaccharides have been reported to exert neuroprotective and antidepressant-like effects in the forced swim test in mice. However, the mechanisms that underlie the antidepressant-like effects of Morinda officinalis oligosaccharides are unclear. Chronic unpredictable stress and forced swim test were used to explore the antidepressant-like effects of Morinda officinalis oligosaccharides and resilience to stress in rats. The phosphoinositide-3 kinase inhibitor LY294002 was microinjected in the medial prefrontal cortex to explore the role of glycogen synthase kinase-3β in the antidepressant-like effects of Morinda officinalis oligosaccharides. The expression of brain-derived neurotrophic factor, phosphorylated-Ser9-glycogen synthase kinase 3β, β-catenin, and synaptic proteins was determined in the medial prefrontal cortex and the orbitofrontal cortex by western blot. We found that Morinda officinalis oligosaccharides effectively ameliorated chronic unpredictable stress-induced depression-like behaviors in the sucrose preference test and forced swim test. The Morinda officinalis oligosaccharides also significantly rescued chronic unpredictable stress-induced abnormalities in the brain-derived neurotrophic factor-glycogen synthase kinase-3β-β-catenin pathway and synaptic protein deficits in the medial prefrontal cortex but not orbitofrontal cortex. The activation of glycogen synthase kinase-3β by the phosphoinositide-3 kinase inhibitor LY294002 abolished the antidepressant-like effects of Morinda officinalis oligosaccharides in the forced swim test. Naïve rats that were treated with Morinda officinalis oligosaccharides exhibited resilience to chronic unpredictable stress, accompanied by increases in the expression of brain-derived neurotrophic factor, phosphorylated-Ser9-glycogen synthase kinase-3β, and β-catenin in the medial prefrontal cortex. Our findings indicate that the brain-derived neurotrophic factor-glycogen synthase kinase-3β-β-catenin pathway in the medial prefrontal cortex may underlie the antidepressant-like effect of Morinda officinalis oligosaccharides and resilience to stress. © The Author 2016. Published by Oxford University Press on behalf of CINP.

Anti-inflammatory and protective effects of MT-031, a novel multitarget MAO-A and AChE/BuChE inhibitor in scopolamine mouse model and inflammatory cells.

PubMed

Liu, Wei; Rabinovich, Alon; Nash, Yuval; Frenkel, Dan; Wang, Yuqiang; Youdim, Moussa B H; Weinreb, Orly

2017-02-01

Previous study demonstrated that the novel multitarget compound, MT-031 preserved in one molecule entity the beneficial properties of its parent drugs, rasagiline and rivastigmine, and exerted high dual potencies of monoamine oxidase-A (MAO-A) and cholinesterase (ChE) inhibition in acute-treated mice and neuroprotective effects against H 2 O 2 -induced neurotoxicity in human neuroblastoma SH-SY5Y cells. The present study aimed to further investigate the anti-inflammatory and protective effects of MT-031 in scopolamine mouse model and inflammatory cell cultures. Our findings demonstrated that once daily chronic administration of MT-031 (5-10 mg/kg) to mice antagonized scopolamine-induced memory and cognitive impairments, displayed brain selective MAO-A and AChE/BuChE inhibition, increased the levels of striatal dopamine (DA), serotonin (5-HT) and norepinephrine and prevented the metabolism of DA and 5-HT. In addition, MT-031 upregulated mRNA expression levels of Bcl-2, the neurotrophic factors, (e.g., brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) and nerve growth factor (NGF)), the antioxidant enzyme catalase and the anti-inflammatory cytokine, neurotrophic tyrosine kinase receptor (Ntrk), and down-regulated the mRNA expression levels of the pro-inflammatory interleukin (IL)-6 in scopolamine-induced mice. In accordance, MT-031 was shown to reduce reactive oxygen species accumulation, increase the levels of anti-inflammatory cytokines, IL-10 and decrease the levels of the pro-inflammatory cytokines, IL-1β, IL-6, IL-17 and interferon-gamma (IFN-γ) in activated mouse splenocytes and microglial cells. Taken together, these pharmacological properties of MT-031 can be of clinical importance for developing this novel multitarget compound as a novel drug candidate for the treatment of Alzheimer's disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

Solution structure and biophysical characterization of the multifaceted signalling effector protein growth arrest specific-1.

PubMed

Rosti, Katja; Goldman, Adrian; Kajander, Tommi

2015-02-28

The protein growth arrest specific-1 (GAS1) was discovered based on its ability to stop the cell cycle. During development it is involved in embryonic patterning, inhibits cell proliferation and mediates cell death, and has therefore been considered as a tumor suppressor. GAS1 is known to signal through two different cell membrane receptors: Rearranged during transformation (RET), and the sonic hedgehog receptor Patched-1. Sonic Hedgehog signalling is important in stem cell renewal and RET mediated signalling in neuronal survival. Disorders in both sonic hedgehog and RET signalling are connected to cancer progression. The neuroprotective effect of RET is controlled by glial cell-derived neurotrophic factor family ligands and glial cell-derived neurotrophic factor receptor alphas (GFRαs). Human Growth arrest specific-1 is a distant homolog of the GFRαs. We have produced and purified recombinant human GAS1 protein, and confirmed that GAS1 is a monomer in solution by static light scattering and small angle X-ray scattering analysis. The low resolution solution structure reveals that GAS1 is more elongated and flexible than the GFRαs, and the homology modelling of the individual domains show that they differ from GFRαs by lacking the amino acids for neurotrophic factor binding. In addition, GAS1 has an extended loop in the N-terminal domain that is conserved in vertebrates after the divergence of fishes and amphibians. We conclude that GAS1 most likely differs from GFRαs functionally, based on comparative structural analysis, while it is able to bind the extracellular part of RET in a neurotrophic factor independent manner, although with low affinity in solution. Our structural characterization indicates that GAS1 differs from GFRα's significantly also in its conformation, which probably reflects the functional differences between GAS1 and the GFRαs.

Managing Disease Risks from Trade: Strategic Behavior with Many Choices and Price Effects.

PubMed

Chitchumnong, Piyayut; Horan, Richard D

2018-03-16

An individual's infectious disease risks, and hence the individual's incentives for risk mitigation, may be influenced by others' risk management choices. If so, then there will be strategic interactions among individuals, whereby each makes his or her own risk management decisions based, at least in part, on the expected decisions of others. Prior work has shown that multiple equilibria could arise in this setting, with one equilibrium being a coordination failure in which individuals make too few investments in protection. However, these results are largely based on simplified models involving a single management choice and fixed prices that may influence risk management incentives. Relaxing these assumptions, we find strategic interactions influence, and are influenced by, choices involving multiple management options and market price effects. In particular, we find these features can reduce or eliminate concerns about multiple equilibria and coordination failure. This has important policy implications relative to simpler models.

Penalized nonparametric scalar-on-function regression via principal coordinates

PubMed Central

Reiss, Philip T.; Miller, David L.; Wu, Pei-Shien; Hua, Wen-Yu

2016-01-01

A number of classical approaches to nonparametric regression have recently been extended to the case of functional predictors. This paper introduces a new method of this type, which extends intermediate-rank penalized smoothing to scalar-on-function regression. In the proposed method, which we call principal coordinate ridge regression, one regresses the response on leading principal coordinates defined by a relevant distance among the functional predictors, while applying a ridge penalty. Our publicly available implementation, based on generalized additive modeling software, allows for fast optimal tuning parameter selection and for extensions to multiple functional predictors, exponential family-valued responses, and mixed-effects models. In an application to signature verification data, principal coordinate ridge regression, with dynamic time warping distance used to define the principal coordinates, is shown to outperform a functional generalized linear model. PMID:29217963

Kinematically redundant arm formulations for coordinated multiple arm implementations

NASA Technical Reports Server (NTRS)

Bailey, Robert W.; Quiocho, Leslie J.; Cleghorn, Timothy F.

1990-01-01

Although control laws for kinematically redundant robotic arms were presented as early as 1969, redundant arms have only recently become recognized as viable solutions to limitations inherent to kinematically sufficient arms. The advantages of run-time control optimization and arm reconfiguration are becoming increasingly attractive as the complexity and criticality of robotic systems continues to progress. A generalized control law for a spatial arm with 7 or more degrees of freedom (DOF) based on Whitney's resolved rate formulation is given. Results from a simulation implementation utilizing this control law are presented. Furthermore, results from a two arm simulation are presented to demonstrate the coordinated control of multiple arms using this formulation.

MicroRNA-8 promotes robust motor axon targeting by coordinate regulation of cell adhesion molecules during synapse development.

PubMed

Lu, Cecilia S; Zhai, Bo; Mauss, Alex; Landgraf, Matthias; Gygi, Stephen; Van Vactor, David

2014-09-26

Neuronal connectivity and specificity rely upon precise coordinated deployment of multiple cell-surface and secreted molecules. MicroRNAs have tremendous potential for shaping neural circuitry by fine-tuning the spatio-temporal expression of key synaptic effector molecules. The highly conserved microRNA miR-8 is required during late stages of neuromuscular synapse development in Drosophila. However, its role in initial synapse formation was previously unknown. Detailed analysis of synaptogenesis in this system now reveals that miR-8 is required at the earliest stages of muscle target contact by RP3 motor axons. We find that the localization of multiple synaptic cell adhesion molecules (CAMs) is dependent on the expression of miR-8, suggesting that miR-8 regulates the initial assembly of synaptic sites. Using stable isotope labelling in vivo and comparative mass spectrometry, we find that miR-8 is required for normal expression of multiple proteins, including the CAMs Fasciclin III (FasIII) and Neuroglian (Nrg). Genetic analysis suggests that Nrg and FasIII collaborate downstream of miR-8 to promote accurate target recognition. Unlike the function of miR-8 at mature larval neuromuscular junctions, at the embryonic stage we find that miR-8 controls key effectors on both sides of the synapse. MiR-8 controls multiple stages of synapse formation through the coordinate regulation of both pre- and postsynaptic cell adhesion proteins.

MicroRNA-8 promotes robust motor axon targeting by coordinate regulation of cell adhesion molecules during synapse development

PubMed Central

Lu, Cecilia S.; Zhai, Bo; Mauss, Alex; Landgraf, Matthias; Gygi, Stephen; Van Vactor, David

2014-01-01

Neuronal connectivity and specificity rely upon precise coordinated deployment of multiple cell-surface and secreted molecules. MicroRNAs have tremendous potential for shaping neural circuitry by fine-tuning the spatio-temporal expression of key synaptic effector molecules. The highly conserved microRNA miR-8 is required during late stages of neuromuscular synapse development in Drosophila. However, its role in initial synapse formation was previously unknown. Detailed analysis of synaptogenesis in this system now reveals that miR-8 is required at the earliest stages of muscle target contact by RP3 motor axons. We find that the localization of multiple synaptic cell adhesion molecules (CAMs) is dependent on the expression of miR-8, suggesting that miR-8 regulates the initial assembly of synaptic sites. Using stable isotope labelling in vivo and comparative mass spectrometry, we find that miR-8 is required for normal expression of multiple proteins, including the CAMs Fasciclin III (FasIII) and Neuroglian (Nrg). Genetic analysis suggests that Nrg and FasIII collaborate downstream of miR-8 to promote accurate target recognition. Unlike the function of miR-8 at mature larval neuromuscular junctions, at the embryonic stage we find that miR-8 controls key effectors on both sides of the synapse. MiR-8 controls multiple stages of synapse formation through the coordinate regulation of both pre- and postsynaptic cell adhesion proteins. PMID:25135978

CUILESS2016: a clinical corpus applying compositional normalization of text mentions.

PubMed

Osborne, John D; Neu, Matthew B; Danila, Maria I; Solorio, Thamar; Bethard, Steven J

2018-01-10

Traditionally text mention normalization corpora have normalized concepts to single ontology identifiers ("pre-coordinated concepts"). Less frequently, normalization corpora have used concepts with multiple identifiers ("post-coordinated concepts") but the additional identifiers have been restricted to a defined set of relationships to the core concept. This approach limits the ability of the normalization process to express semantic meaning. We generated a freely available corpus using post-coordinated concepts without a defined set of relationships that we term "compositional concepts" to evaluate their use in clinical text. We annotated 5397 disorder mentions from the ShARe corpus to SNOMED CT that were previously normalized as "CUI-less" in the "SemEval-2015 Task 14" shared task because they lacked a pre-coordinated mapping. Unlike the previous normalization method, we do not restrict concept mappings to a particular set of the Unified Medical Language System (UMLS) semantic types and allow normalization to occur to multiple UMLS Concept Unique Identifiers (CUIs). We computed annotator agreement and assessed semantic coverage with this method. We generated the largest clinical text normalization corpus to date with mappings to multiple identifiers and made it freely available. All but 8 of the 5397 disorder mentions were normalized using this methodology. Annotator agreement ranged from 52.4% using the strictest metric (exact matching) to 78.2% using a hierarchical agreement that measures the overlap of shared ancestral nodes. Our results provide evidence that compositional concepts can increase semantic coverage in clinical text. To our knowledge we provide the first freely available corpus of compositional concept annotation in clinical text.

Stoichiometric Control of Multiple Different Tectons in Coordination-Driven Self-assembly

PubMed Central

Lee, Junseong; Ghosh, Koushik; Stang, Peter J.

2009-01-01

We present a general strategy for the synthesis of stable, multi-component fused polygon complexes where coordination-driven self-assembly allows for single supramolecular species can be formed from multi-component self-assembly and the shape of the obtained polygons can be controlled by simply changing the ratio of individual components. The compounds are characterized by Multinuclear NMR, ESI Mass spectrometry. PMID:19663439

View-Invariant Object Category Learning, Recognition, and Search: How Spatial and Object Attention are Coordinated Using Surface-Based Attentional Shrouds

ERIC Educational Resources Information Center

Fazl, Arash; Grossberg, Stephen; Mingolla, Ennio

2009-01-01

How does the brain learn to recognize an object from multiple viewpoints while scanning a scene with eye movements? How does the brain avoid the problem of erroneously classifying parts of different objects together? How are attention and eye movements intelligently coordinated to facilitate object learning? A neural model provides a unified…

Optimizing clinical and organizational practice in cancer survivor transitions between specialized oncology and primary care teams: a realist evaluation of multiple case studies.

PubMed

Tremblay, Dominique; Prady, Catherine; Bilodeau, Karine; Touati, Nassera; Chouinard, Maud-Christine; Fortin, Martin; Gaboury, Isabelle; Rodrigue, Jean; L'Italien, Marie-France

2017-12-16

Cancer is now viewed as a chronic disease, presenting challenges to follow-up and survivorship care. Models to shift from haphazard, suboptimal and fragmented episodes of care to an integrated cancer care continuum must be developed, tested and implemented. Numerous studies demonstrate improved care when follow-up is assured by both oncology and primary care providers rather than either group alone. However, there is little data on the roles assumed by specialized oncology teams and primary care providers and the extent to which they work together. This study aims to develop, pilot test and measure outcomes of an innovative risk-based coordinated cancer care model for patients transitioning from specialized oncology teams to primary care providers. This multiple case study using a sequential mixed-methods design rests on a theory-driven realist evaluation approach to understand how transitions might be improved. The cases are two health regions in Quebec, Canada, defined by their geographic territory. Each case includes a Cancer Centre and three Family Medicine Groups selected based on differences in their determining characteristics. Qualitative data will be collected from document review (scientific journal, grey literature, local documentation), semi-directed interviews with key informants, and observation of care coordination practices. Qualitative data will be supplemented with a survey to measure the outcome of the coordinated model among providers (scope of practice, collaboration, relational coordination, leadership) and patients diagnosed with breast, colorectal or prostate cancer (access to care, patient-centredness, communication, self-care, survivorship profile, quality of life). Results from descriptive and regression analyses will be triangulated with thematic analysis of qualitative data. Qualitative, quantitative, and mixed methods data will be interpreted within and across cases in order to identify context-mechanism associations that explain outcomes. The study will provide empirical data on a risk-based coordinated model of cancer care to guide actions at different levels in the health system. This in-depth multiple case study using a realist approach considers both the need for context-specific intervention research and the imperative to address research gaps regarding coordinated models of cancer care.

Lessons Learned In Developing Multiple Distributed Planning Systems for the International Space Station

NASA Technical Reports Server (NTRS)

Maxwell, Theresa G.; McNair, Ann R. (Technical Monitor)

2002-01-01

The planning processes for the International Space Station (ISS) Program are quite complex. Detailed mission planning for ISS on-orbit operations is a distributed function. Pieces of the on-orbit plan are developed by multiple planning organizations, located around the world, based on their respective expertise and responsibilities. The "pieces" are then integrated to yield the final detailed plan that will be executed onboard the ISS. Previous space programs have not distributed the planning and scheduling functions to this extent. Major ISS planning organizations are currently located in the United States (at both the NASA Johnson Space Center (JSC) and NASA Marshall Space Flight Center (MSFC)), in Russia, in Europe, and in Japan. Software systems have been developed by each of these planning organizations to support their assigned planning and scheduling functions. Although there is some cooperative development and sharing of key software components, each planning system has been tailored to meet the unique requirements and operational environment of the facility in which it operates. However, all the systems must operate in a coordinated fashion in order to effectively and efficiently produce a single integrated plan of ISS operations, in accordance with the established planning processes. This paper addresses lessons learned during the development of these multiple distributed planning systems, from the perspective of the developer of one of the software systems. The lessons focus on the coordination required to allow the multiple systems to operate together, rather than on the problems associated with the development of any particular system. Included in the paper is a discussion of typical problems faced during the development and coordination process, such as incompatible development schedules, difficulties in defining system interfaces, technical coordination and funding for shared tools, continually evolving planning concepts/requirements, programmatic and budget issues, and external influences. Techniques that mitigated some of these problems will also be addressed, along with recommendations for any future programs involving the development of multiple planning and scheduling systems. Many of these lessons learned are not unique to the area of planning and scheduling systems, so may be applied to other distributed ground systems that must operate in concert to successfully support space mission operations.

Lessons Learned in Developing Multiple Distributed Planning Systems for the International Space Station

NASA Technical Reports Server (NTRS)

Maxwell, Theresa G.

2002-01-01

The planning processes for the International Space Station (ISS) Program are quite complex. Detailed mission planning for ISS on-orbit operations is a distributed function. Pieces of the on-orbit plan are developed by multiple planning organizations, located around the world, based on their respective expertise and responsibilities. The pieces are then integrated to yield the final detailed plan that will be executed onboard the ISS. Previous space programs have not distributed the planning and scheduling functions to this extent. Major ISS planning organizations are currently located in the United States (at both the NASA Johnson Space Center (JSC) and NASA Marshall Space Flight Center (MSFC)), in Russia, in Europe, and in Japan. Software systems have been developed by each of these planning organizations to support their assigned planning and scheduling functions. Although there is some cooperative development and sharing of key software components, each planning system has been tailored to meet the unique requirements and operational environment of the facility in which it operates. However, all the systems must operate in a coordinated fashion in order to effectively and efficiently produce a single integrated plan of ISS operations, in accordance with the established planning processes. This paper addresses lessons learned during the development of these multiple distributed planning systems, from the perspective of the developer of one of the software systems. The lessons focus on the coordination required to allow the multiple systems to operate together, rather than on the problems associated with the development of any particular system. Included in the paper is a discussion of typical problems faced during the development and coordination process, such as incompatible development schedules, difficulties in defining system interfaces, technical coordination and funding for shared tools, continually evolving planning concepts/requirements, programmatic and budget issues, and external influences. Techniques that mitigated some of these problems will also be addressed, along with recommendations for any future programs involving the development of multiple planning and scheduling systems. Many of these lessons learned are not unique to the area of planning and scheduling systems, so may be applied to other distributed ground systems that must operate in concert to successfully support space mission operations.

Co-immobilization of multiple enzymes by metal coordinated nucleotide hydrogel nanofibers: improved stability and an enzyme cascade for glucose detection.

PubMed

Liang, Hao; Jiang, Shuhui; Yuan, Qipeng; Li, Guofeng; Wang, Feng; Zhang, Zijie; Liu, Juewen

2016-03-21

Preserving enzyme activity and promoting synergistic activity via co-localization of multiple enzymes are key topics in bionanotechnology, materials science, and analytical chemistry. This study reports a facile method for co-immobilizing multiple enzymes in metal coordinated hydrogel nanofibers. Specifically, four types of protein enzymes, including glucose oxidase, Candida rugosa lipase, α-amylase, and horseradish peroxidase, were respectively encapsulated in a gel nanofiber made of Zn(2+) and adenosine monophosphate (AMP) with a simple mixing step. Most enzymes achieved quantitative loading and retained full activity. At the same time, the entrapped enzymes were more stable against temperature variation (by 7.5 °C), protease attack, extreme pH (by 2-fold), and organic solvents. After storing for 15 days, the entrapped enzyme still retained 70% activity while the free enzyme nearly completely lost its activity. Compared to nanoparticles formed with AMP and lanthanide ions, the nanofiber gels allowed much higher enzyme activity. Finally, a highly sensitive and selective biosensor for glucose was prepared using the gel nanofiber to co-immobilize glucose oxidase and horseradish peroxidase for an enzyme cascade system. A detection limit of 0.3 μM glucose with excellent selectivity was achieved. This work indicates that metal coordinated materials using nucleotides are highly useful for interfacing with biomolecules.

Brg1 coordinates multiple processes during retinogenesis and is a tumor suppressor in retinoblastoma

DOE PAGES

Aldiri, Issam; Ajioka, Itsuki; Xu, Beisi; ...

2015-12-01

Retinal development requires precise temporal and spatial coordination of cell cycle exit, cell fate specification, cell migration and differentiation. When this process is disrupted, retinoblastoma, a developmental tumor of the retina, can form. Epigenetic modulators are central to precisely coordinating developmental events, and many epigenetic processes have been implicated in cancer. Studying epigenetic mechanisms in development is challenging because they often regulate multiple cellular processes; therefore, elucidating the primary molecular mechanisms involved can be difficult. Here we explore the role of Brg1 (Smarca4) in retinal development and retinoblastoma in mice using molecular and cellular approaches. Brg1 was found to regulatemore » retinal size by controlling cell cycle length, cell cycle exit and cell survival during development. Brg1 was not required for cell fate specification but was required for photoreceptor differentiation and cell adhesion/polarity programs that contribute to proper retinal lamination during development. The combination of defective cell differentiation and lamination led to retinal degeneration in Brg1-deficient retinae. Despite the hypocellularity, premature cell cycle exit, increased cell death and extended cell cycle length, retinal progenitor cells persisted in Brg1-deficient retinae, making them more susceptible to retinoblastoma. In conclusion, ChIP-Seq analysis suggests that Brg1 might regulate gene expression through multiple mechanisms.« less

Brg1 coordinates multiple processes during retinogenesis and is a tumor suppressor in retinoblastoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Aldiri, Issam; Ajioka, Itsuki; Xu, Beisi

Retinal development requires precise temporal and spatial coordination of cell cycle exit, cell fate specification, cell migration and differentiation. When this process is disrupted, retinoblastoma, a developmental tumor of the retina, can form. Epigenetic modulators are central to precisely coordinating developmental events, and many epigenetic processes have been implicated in cancer. Studying epigenetic mechanisms in development is challenging because they often regulate multiple cellular processes; therefore, elucidating the primary molecular mechanisms involved can be difficult. Here we explore the role of Brg1 (Smarca4) in retinal development and retinoblastoma in mice using molecular and cellular approaches. Brg1 was found to regulatemore » retinal size by controlling cell cycle length, cell cycle exit and cell survival during development. Brg1 was not required for cell fate specification but was required for photoreceptor differentiation and cell adhesion/polarity programs that contribute to proper retinal lamination during development. The combination of defective cell differentiation and lamination led to retinal degeneration in Brg1-deficient retinae. Despite the hypocellularity, premature cell cycle exit, increased cell death and extended cell cycle length, retinal progenitor cells persisted in Brg1-deficient retinae, making them more susceptible to retinoblastoma. In conclusion, ChIP-Seq analysis suggests that Brg1 might regulate gene expression through multiple mechanisms.« less

From Coordination Cages to a Stable Crystalline Porous Hydrogen-Bonded Framework

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ju, Zhanfeng; Liu, Guoliang; Chen, Yu-Sheng

2017-03-20

A stable framework has been constructed through multiple charge-assisted H-bonds between cationic coordination cages and chloride ions. The framework maintained its original structure upon desolvation, which has been established by single-crystal structure analysis. This is the first fully characterized stable porous framework based on coordination cages after desolvation, with a moderately high Brunauer–Emmett–Teller (BET) surface area of 1201 m2 g-1. This work will not only give a light to construct stable porous frameworks based on coordination cages and thus broaden their applications, but will also provide a new avenue to the assembly of other porous materials such as porous organicmore » cages and hydrogen-bonded organic frameworks (HOFs) through non covalent bonds.« less

Human neuroblastoma growth inhibitory factor (h-NGIF), derived from human astrocytoma conditioned medium, has neurotrophic properties.

PubMed

Eksioglu, Y Z; Iida, J; Asai, K; Ueki, T; Nakanishi, K; Isobe, I; Yamagata, K; Kato, T

1994-05-02

Investigations on the general characteristics of human astrocytoma cell line NAC-1 revealed neuroblastoma growth inhibitory activity in conditioned medium. Neuroblastoma growth inhibitory factor (NGIF) was partially purified by Econo Q, Econo CM, and Superose 12 column chromatography. The protein is weakly basic with an estimated M(r) of 120,000, possibly having an M(r) 60,000 dimeric structure. NGIF inhibits the growth of human neuroblastoma cell lines but has no effect on morphology nor does it produce any change in the growth of human glioblastoma cell lines. Interestingly, NGIF appears to promote survival and neurite outgrowth of embryonal rat cortical neurons. These neurotrophic properties suggest a role for NGIF in the development of the nervous system.

Regional differences in the expression of brain-derived neurotrophic factor (BDNF) pro-peptide, proBDNF and preproBDNF in the brain confer stress resilience.

PubMed

Yang, Bangkun; Yang, Chun; Ren, Qian; Zhang, Ji-Chun; Chen, Qian-Xue; Shirayama, Yukihiko; Hashimoto, Kenji

2016-12-01

Using learned helplessness (LH) model of depression, we measured protein expression of brain-derived neurotrophic factor (BDNF) pro-peptide, BDNF precursors (proBDNF and preproBDNF) in the brain regions of LH (susceptible) and non-LH rats (resilience). Expression of preproBDNF, proBDNF and BDNF pro-peptide in the medial prefrontal cortex of LH rats, but not non-LH rats, was significantly higher than control rats, although expression of these proteins in the nucleus accumbens of LH rats was significantly lower than control rats. This study suggests that regional differences in conversion of BDNF precursors into BDNF and BDNF pro-peptide by proteolytic cleavage may contribute to stress resilience.

Effects of naringin, a flavanone glycoside in grapefruits and citrus fruits, on the nigrostriatal dopaminergic projection in the adult brain

PubMed Central

Jung, Un Ju; Kim, Sang Ryong

2014-01-01

Recently, we have demonstrated the ability of naringin, a well-known flavanone glycoside of grapefruits and citrus fruits, to prevent neurodegeneration in a neurotoxin model of Parkinson's disease. Intraperitoneal injection of naringin protected the nigrostriatal dopaminergic projection by increasing glial cell line-derived neurotrophic factor expression and decreasing the level of tumor necrosis factor-alpha in dopaminergic neurons and microglia, respectively. These results suggest that naringin can impart to the adult dopaminergic neurons the ability to produce glial cell line-derived neurotrophic factor against Parkinson's disease with anti-inflammatory effects. Based on these results, we would like to describe an important perspective on its possibility as a therapeutic agent for Parkinson's disease. PMID:25317167

Zinc Interactions With Brain-Derived Neurotrophic Factor and Related Peptide Fragments.

PubMed

Travaglia, A; La Mendola, D

2017-01-01

Brain-derived neurotrophic factor (BDNF) is a neurotrophin essential for neuronal development and survival, synaptic plasticity, and cognitive function. Dysregulation of BDNF signaling is involved in several neurodegenerative disorders, including Alzheimer's disease. Alteration of metal ion homeostasis is observed both in normal aging and in many neurodegenerative diseases. Interestingly, there is a significant overlap between brain areas characterized by metal ion dyshomeostasis and those where BDNF exerts its biological activity. Therefore, it is reasonable to speculate that metal ions, especially zinc, can modulate the activity of BDNF. The synthesis of BDNF peptidomimetic can be helpful both to understand the molecular interaction of BDNF with metal ions and to develop new drugs for neurodegenerative diseases. © 2017 Elsevier Inc. All rights reserved.

Brain-derived neurotrophic factor and Alzheimer's disease: physiopathology and beyond.

PubMed

Diniz, Breno Satler; Teixeira, Antonio Lucio

2011-12-01

Brain-derived neurotrophic factor (BDNF) is the most widely distributed neurotrophin in the central nervous system where it plays several pivotal roles in synaptic plasticity and neuronal survival. As a consequence, BDNF became a key target in the physiopathology of several neurological and psychiatric diseases. Recent studies have reported altered levels of BDNF in the circulation, i.e. serum or plasma, of patients with Alzheimer's disease (AD), and low BDNF levels in the CSF as predictor of future cognitive decline in healthy older subjects. Altered BDNF circulating levels have also been reported in other neurodegenerative and psychiatric disorders, hampering its use as a specific biomarker for AD. Therefore, BDNF seems to be an unspecific biomarker of neuropsychiatric disorders marked by neurodegenerative changes.

Extended H2 synthesis for multiple degree-of-freedom controllers

NASA Technical Reports Server (NTRS)

Hampton, R. David; Knospe, Carl R.

1992-01-01

H2 synthesis techniques are developed for a general multiple-input-multiple-output (MIMO) system subject to both stochastic and deterministic disturbances. The H2 synthesis is extended by incorporation of anticipated disturbances power-spectral-density information into the controller-design process, as well as by frequency weightings of generalized coordinates and control inputs. The methodology is applied to a simple single-input-multiple-output (SIMO) problem, analogous to the type of vibration isolation problem anticipated in microgravity research experiments.

Active Joint Mechanism Driven by Multiple Actuators Made of Flexible Bags: A Proposal of Dual Structural Actuator

PubMed Central

Inou, Norio

2013-01-01

An actuator is required to change its speed and force depending on the situation. Using multiple actuators for one driving axis is one of the possible solutions; however, there is an associated problem of output power matching. This study proposes a new active joint mechanism using multiple actuators. Because the actuator is made of a flexible bag, it does not interfere with other actuators when it is depressurized. The proposed joint achieved coordinated motion of multiple actuators. This report also discusses a new actuator which has dual cylindrical structure. The cylinders are composed of flexible bags with different diameters. The joint torque is estimated based on the following factors: empirical formula for the flexible actuator torque, geometric relationship between the joint and the actuator, and the principle of virtual work. The prototype joint mechanism achieves coordinated motion of multiple actuators for one axis. With this motion, small inner actuator contributes high speed motion, whereas large outer actuator generates high torque. The performance of the prototype joint is examined by speed and torque measurements. The joint showed about 30% efficiency at 2.0 Nm load torque under 0.15 MPa air input. PMID:24385868

Active joint mechanism driven by multiple actuators made of flexible bags: a proposal of dual structural actuator.

PubMed

Kimura, Hitoshi; Matsuzaki, Takuya; Kataoka, Mokutaro; Inou, Norio

2013-01-01

An actuator is required to change its speed and force depending on the situation. Using multiple actuators for one driving axis is one of the possible solutions; however, there is an associated problem of output power matching. This study proposes a new active joint mechanism using multiple actuators. Because the actuator is made of a flexible bag, it does not interfere with other actuators when it is depressurized. The proposed joint achieved coordinated motion of multiple actuators. This report also discusses a new actuator which has dual cylindrical structure. The cylinders are composed of flexible bags with different diameters. The joint torque is estimated based on the following factors: empirical formula for the flexible actuator torque, geometric relationship between the joint and the actuator, and the principle of virtual work. The prototype joint mechanism achieves coordinated motion of multiple actuators for one axis. With this motion, small inner actuator contributes high speed motion, whereas large outer actuator generates high torque. The performance of the prototype joint is examined by speed and torque measurements. The joint showed about 30% efficiency at 2.0 Nm load torque under 0.15 MPa air input.

Stress Physiology in Infancy and Early Childhood: Cortisol Flexibility, Attunement and Coordination.

PubMed

Atkinson, L; Jamieson, B; Khoury, J; Ludmer, J; Gonzalez, A

2016-08-01

Research on stress physiology in infancy has assumed increasing importance due to its lifelong implications. In this review, we focus on measurement of hypothalamic-pituitary-adrenal (HPA) function, in particular, and on complementary autonomic processes. We suggest that the measure of HPA function has been overly exclusive, focusing on individual reactivity to single, pragmatically selected laboratory challenges. We advocate use of multiple, strategically chosen challenges and within-subject designs. By administering one challenge that typically does not provoke reactivity and another that does, it is possible to represent allostatic load in terms of "flexibility," the capacity to titrate response to challenge. We also recommend assessing infant reactivity in the context of the primary caregiver's physiological function. Infant-mother "attunement" is central to developmental psychology, permeating diverse developmental domains with varied consequences. A review of adrenocortical attunement suggests that attunement is a reliable process, manifest across varied populations. However, attunement appears stronger in the context of more highly stressful circumstances, such that administration of multiple, selected challenges may help evaluate the degree to which individuals titrate attunement to challenge and determine the correlates of this differential attunement. Finally, we advocate studying the "coordination" of HPA function with other aspects of stress physiology and variation in the degree of this coordination. The use of multiple stressors is important here because each stress system is differentially sensitive to different types of challenge. Therefore, use of single stressors in between-subject designs impedes full recognition of the role played by each system. Overall, we recommend measure of flexibility, attunement, and coordination in the context of multiple challenges to capture allostasis in environmental and physiological context. The simultaneous use of such inclusive and integrative metrics may yield more reliable findings than has hitherto been the case. The interrelation of these metrics can be understood in the context of the adaptive calibration model.. © 2016 British Society for Neuroendocrinology.

Teamwork methods for accountable care: relational coordination and TeamSTEPPS®.

PubMed

Gittell, Jody Hoffer; Beswick, Joanne; Goldmann, Don; Wallack, Stanley S

2015-01-01

To deliver greater value in the accountable care context, the Institute of Medicine argues for a culture of teamwork at multiple levels--across professional and organizational siloes and with patients and their families and communities. The logic of performance improvement is that data are needed to target interventions and to assess their impact. We argue that efforts to build teamwork will benefit from teamwork measures that provide diagnostic information regarding the current state and teamwork interventions that can respond to the opportunities identified in the current state. We identify teamwork measures and teamwork interventions that are validated and that can work across multiple levels of teamwork. We propose specific ways to combine them for optimal effectiveness. We review measures of teamwork documented by Valentine, Nembhard, and Edmondson and select those that they identified as satisfying the four criteria for psychometric validation and as being unbounded and therefore able to measure teamwork across multiple levels. We then consider teamwork interventions that are widely used in the U.S. health care context, are well validated based on their association with outcomes, and are capable of working at multiple levels of teamwork. We select the top candidate in each category and propose ways to combine them for optimal effectiveness. We find relational coordination is a validated multilevel teamwork measure and TeamSTEPPS® is a validated multilevel teamwork intervention and propose specific ways for the relational coordination measure to enhance the TeamSTEPPS intervention. Health care systems and change agents seeking to respond to the challenges of accountable care can use TeamSTEPPS as a validated multilevel teamwork intervention methodology, enhanced by relational coordination as a validated multilevel teamwork measure with diagnostic capacity to pinpoint opportunities for improving teamwork along specific dimensions (e.g., shared knowledge, timely communication) and in specific role relationships (e.g., nurse/medical assistant, emergency unit/medical unit, primary care/specialty care).

Validation of 2 New Measures of Continuity of Care Based on Year-to-Year Follow-up With Known Providers of Health Care

PubMed Central

Tousignant, Pierre; Diop, Mamadou; Fournier, Michel; Roy, Yves; Haggerty, Jeannie; Hogg, William; Beaulieu, Marie-Dominique

2014-01-01

PURPOSE In a primary care context favoring group practices, we assessed the validity of 2 new continuity measures (both versions of known provider continuity, KPC) that capture the concentration of care over time from multiple physicians (multiple provider continuity, KPC-MP) or from the physician seen most often (personal provider continuity, KPC-PP). METHODS Patients with diabetes or cardiovascular disease (N = 765) were approached in the waiting rooms of 28 primary care clinics in 3 regions of the province of Quebec, Canada; answered a survey questionnaire measuring relational continuity, interpersonal communication, coordination within the clinic, coordination with specialists, and overall coordination; and gave permission for their medical records to be reviewed and their medical services utilization data for the previous 2 years to be accessed to measure KPC. Using generalized linear mixed models, we assessed the association between KPC and the patients’ responses. RESULTS Among the 5 different patient-reported measures or their combination, KPC-MP was significantly related with overall coordination of care: for high continuity, the odds ratio (OR) = 2.02 (95% CI, 1.33–3.07), and for moderate continuity, OR = 1.61 (95% CI, 1.06–2.46). KPC-MP was also related with the combined continuity score: for high continuity, OR = 1.52 (95% CI, 1.11–2.09), and for moderate continuity, OR = 1.48 (95% CI, 1.10–2.00). KPC-PP was not significantly associated with any of the survey measures. CONCLUSIONS The KPC-MP measure, based on readily available administrative data, is associated with patient-perceived overall coordination of care among multiple physicians. KPC measures are potentially a valuable and low-cost way to follow the effects of changes favoring group practice on continuity of care for entire populations. They are easy to replicate over time and across jurisdictions. PMID:25384820

Coordinating a Large, Amalgamated REU Program with Multiple Funding Sources

ERIC Educational Resources Information Center

Fiorini, Eugene; Myers, Kellen; Naqvi, Yusra

2017-01-01

In this paper, we discuss the challenges of organizing a large REU program amalgamated from multiple funding sources, including diverse participants, mentors, and research projects. We detail the program's structure, activities, and recruitment, and we hope to demonstrate that the organization of this REU is not only beneficial to its…

"In Our Corner": A Qualitative Descriptive Study of Patient Engagement in a Community-Based Care Coordination Program.

PubMed

Sefcik, Justine S; Petrovsky, Darina; Streur, Megan; Toles, Mark; O'Connor, Melissa; Ulrich, Connie M; Marcantonio, Sherry; Coburn, Ken; Naylor, Mary D; Moriarty, Helene

2018-03-01

The purpose of this study was to explore participants' experience in the Health Quality Partners (HQP) Care Coordination Program that contributed to their continued engagement. Older adults with multiple chronic conditions often have limited engagement in health care services and face fragmented health care delivery. This can lead to increased risk for disability, mortality, poor quality of life, and increased health care utilization. A qualitative descriptive design with two focus groups was conducted with a total of 20 older adults enrolled in HQP's Care Coordination Program. Conventional content analysis was the analytical technique. The overarching theme resulting from the analysis was "in our corner," with subthemes "opportunities to learn and socialize" and "dedicated nurses," suggesting that these are the primary contributing factors to engagement in HQP's Care Coordination Program. Study findings suggest that nurses play an integral role in patient engagement among older adults enrolled in a care coordination program.

Analytical Dynamics and Nonrigid Spacecraft Simulation

NASA Technical Reports Server (NTRS)

Likins, P. W.

1974-01-01

Application to the simulation of idealized spacecraft are considered both for multiple-rigid-body models and for models consisting of combination of rigid bodies and elastic bodies, with the elastic bodies being defined either as continua, as finite-element systems, or as a collection of given modal data. Several specific examples are developed in detail by alternative methods of analytical mechanics, and results are compared to a Newton-Euler formulation. The following methods are developed from d'Alembert's principle in vector form: (1) Lagrange's form of d'Alembert's principle for independent generalized coordinates; (2) Lagrange's form of d'Alembert's principle for simply constrained systems; (3) Kane's quasi-coordinate formulation of D'Alembert's principle; (4) Lagrange's equations for independent generalized coordinates; (5) Lagrange's equations for simply constrained systems; (6) Lagrangian quasi-coordinate equations (or the Boltzmann-Hamel equations); (7) Hamilton's equations for simply constrained systems; and (8) Hamilton's equations for independent generalized coordinates.

Speciation of aqueous Ni(II)-carboxylate and Ni(II)-fulvic acid solutions: Combined ATR-FTIR and XAFS analysis

NASA Astrophysics Data System (ADS)

Strathmann, Timothy J.; Myneni, Satish C. B.

2004-09-01

Aqueous solutions containing Ni(II) and a series of structurally related carboxylic acids were analyzed using attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR) and Ni K-edge X-ray absorption fine structure spectroscopy (XAFS). XAFS spectra were also collected for solutions containing Ni 2+ and chelating ligands (ethylenediaminetetraacetic acid, nitrilotriacetic acid (NTA)) as well as soil fulvic acid. Limited spectral changes are observed for aqueous Ni(II) complexes with monocarboxylates (formate, acetate) and long-chain polycarboxylates (succinate, tricarballylate), where individual donor groups are separated by multiple bridging methylene groups. These spectral changes indicate weak interactions between Ni(II) and carboxylates, and the trends are similar to some earlier reports for crystalline Ni(II)-acetate solids, for which X-ray crystallography studies have indicated monodentate Ni(II)-carboxylate coordination. Nonetheless, electrostatic or outer-sphere coordination cannot be ruled out for these complexes. However, spectral changes observed for short-chain dicarboxylates (oxalate, malonate) and carboxylates that contain an alcohol donor group adjacent to one of the carboxylate groups (lactate, malate, citrate) demonstrate inner-sphere metal coordination by multiple donor groups. XAFS spectral fits of Ni(II) solutions containing soil fulvic acid are consistent with inner-sphere Ni(II) coordination by one or more carboxylate groups, but spectra are noisy and outer-sphere modes of coordination cannot be ruled out. These molecular studies refine our understanding of the interactions between carboxylates and weakly complexing divalent transition metals, such as Ni(II).

Distributed Learning, Extremum Seeking, and Model-Free Optimization for the Resilient Coordination of Multi-Agent Adversarial Groups

DTIC Science & Technology

2016-09-07

been demonstrated on maximum power point tracking for photovoltaic arrays and for wind turbines . 3. ES has recently been implemented on the Mars...high-dimensional optimization problems . Extensions and applications of these techniques were developed during the realization of the project. 15...studied problems of dynamic average consensus and a class of unconstrained continuous-time optimization algorithms for the coordination of multiple

Shared periodic performer movements coordinate interactions in duo improvisations

PubMed Central

Jakubowski, Kelly; Moran, Nikki; Keller, Peter E.

2018-01-01

Human interaction involves the exchange of temporally coordinated, multimodal cues. Our work focused on interaction in the visual domain, using music performance as a case for analysis due to its temporally diverse and hierarchical structures. We made use of two improvising duo datasets—(i) performances of a jazz standard with a regular pulse and (ii) non-pulsed, free improvizations—to investigate whether human judgements of moments of interaction between co-performers are influenced by body movement coordination at multiple timescales. Bouts of interaction in the performances were manually annotated by experts and the performers’ movements were quantified using computer vision techniques. The annotated interaction bouts were then predicted using several quantitative movement and audio features. Over 80% of the interaction bouts were successfully predicted by a broadband measure of the energy of the cross-wavelet transform of the co-performers’ movements in non-pulsed duos. A more complex model, with multiple predictors that captured more specific, interacting features of the movements, was needed to explain a significant amount of variance in the pulsed duos. The methods developed here have key implications for future work on measuring visual coordination in musical ensemble performances, and can be easily adapted to other musical contexts, ensemble types and traditions. PMID:29515867

GPS-Free Localization Algorithm for Wireless Sensor Networks

PubMed Central

Wang, Lei; Xu, Qingzheng

2010-01-01

Localization is one of the most fundamental problems in wireless sensor networks, since the locations of the sensor nodes are critical to both network operations and most application level tasks. A GPS-free localization scheme for wireless sensor networks is presented in this paper. First, we develop a standardized clustering-based approach for the local coordinate system formation wherein a multiplication factor is introduced to regulate the number of master and slave nodes and the degree of connectivity among master nodes. Second, using homogeneous coordinates, we derive a transformation matrix between two Cartesian coordinate systems to efficiently merge them into a global coordinate system and effectively overcome the flip ambiguity problem. The algorithm operates asynchronously without a centralized controller; and does not require that the location of the sensors be known a priori. A set of parameter-setting guidelines for the proposed algorithm is derived based on a probability model and the energy requirements are also investigated. A simulation analysis on a specific numerical example is conducted to validate the mathematical analytical results. We also compare the performance of the proposed algorithm under a variety multiplication factor, node density and node communication radius scenario. Experiments show that our algorithm outperforms existing mechanisms in terms of accuracy and convergence time. PMID:22219694

Current progress in use of adipose derived stem cells in peripheral nerve regeneration

PubMed Central

Zack-Williams, Shomari DL; Butler, Peter E; Kalaskar, Deepak M

2015-01-01

Unlike central nervous system neurons; those in the peripheral nervous system have the potential for full regeneration after injury. Following injury, recovery is controlled by schwann cells which replicate and modulate the subsequent immune response. The level of nerve recovery is strongly linked to the severity of the initial injury despite the significant advancements in imaging and surgical techniques. Multiple experimental models have been used with varying successes to augment the natural regenerative processes which occur following nerve injury. Stem cell therapy in peripheral nerve injury may be an important future intervention to improve the best attainable clinical results. In particular adipose derived stem cells (ADSCs) are multipotent mesenchymal stem cells similar to bone marrow derived stem cells, which are thought to have neurotrophic properties and the ability to differentiate into multiple lineages. They are ubiquitous within adipose tissue; they can form many structures resembling the mature adult peripheral nervous system. Following early in vitro work; multiple small and large animal in vivo models have been used in conjunction with conduits, autografts and allografts to successfully bridge the peripheral nerve gap. Some of the ADSC related neuroprotective and regenerative properties have been elucidated however much work remains before a model can be used successfully in human peripheral nerve injury (PNI). This review aims to provide a detailed overview of progress made in the use of ADSC in PNI, with discussion on the role of a tissue engineered approach for PNI repair. PMID:25621105

Enhancing nerve regeneration in the peripheral nervous system using polymeric scaffolds, stem cell engineering and nanoparticle delivery system

NASA Astrophysics Data System (ADS)

Sharma, Anup Dutt

Peripheral nerve regeneration is a complex biological process responsible for regrowth of neural tissue following a nerve injury. The main objective of this project was to enhance peripheral nerve regeneration using interdisciplinary approaches involving polymeric scaffolds, stem cell therapy, drug delivery and high content screening. Biocompatible and biodegradable polymeric materials such as poly (lactic acid) were used for engineering conduits with micropatterns capable of providing mechanical support and orientation to the regenerating axons and polyanhydrides for fabricating nano/microparticles for localized delivery of neurotrophic growth factors and cytokines at the site of injury. Transdifferentiated bone marrow stromal cells or mesenchymal stem cells (MSCs) were used as cellular replacements for lost native Schwann cells (SCs) at the injured nerve tissue. MSCs that have been transdifferentiated into an SC-like phenotype were tested as a substitute for the myelinating SCs. Also, genetically modified MSCs were engineered to hypersecrete brain- derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) to secrete therapeutic factors which Schwann cell secrete. To further enhance the regeneration, nerve growth factor (NGF) and interleukin-4 (IL4) releasing polyanhydrides nano/microparticles were fabricated and characterized in vitro for their efficacy. Synergistic use of these proposed techniques was used for fabricating a multifunctional nerve regeneration conduit which can be used as an efficient tool for enhancing peripheral nerve regeneration.

A Standardized Chinese Herbal Decoction, Kai-Xin-San, Restores Decreased Levels of Neurotransmitters and Neurotrophic Factors in the Brain of Chronic Stress-Induced Depressive Rats

PubMed Central

Zhu, Kevin Yue; Mao, Qing-Qiu; Ip, Siu-Po; Choi, Roy Chi-Yan; Dong, Tina Ting-Xia; Lau, David Tai-Wai; Tsim, Karl Wah-Keung

2012-01-01

Kai-xin-san (KXS), a Chinese herbal decoction being prescribed by Sun Simiao in Beiji Qianjin Yaofang about 1400 years ago, contains Ginseng Radix et Rhizoma, Polygalae Radix, Acori tatarinowii Rhizoma, and Poria. KXS has been used to treat stress-related psychiatric disease with the symptoms of depression and forgetfulness in ancient China until today. However, the mechanism of its antidepression action is still unknown. Here, the chronic mild-stress-(CMS-) induced depressive rats were applied in exploring the action mechanisms of KXS treatment. Daily intragastric administration of KXS for four weeks significantly alleviated the CMS-induced depressive symptoms displayed by enhanced sucrose consumption. In addition, the expressions of those molecular bio-markers relating to depression in rat brains were altered by the treatment of KXS. These KXS-regulated brain biomarkers included: (i) the levels of dopamine, norepinephrine, and serotonin (ii) the transcript levels of proteins relating to neurotransmitter metabolism; (iii) the transcript levels of neurotrophic factors and their receptors. The results suggested that the anti-depressant-like action of KXS might be mediated by an increase of neurotransmitters and expression of neurotrophic factors and its corresponding receptors in the brain. Thus, KXS could serve as alternative medicine, or health food supplement, for patients suffering from depression. PMID:22973399

Neuro-peptide treatment with Cerebrolysin improves the survival of neural stem cell grafts in an APP transgenic model of Alzheimer disease.

PubMed

Rockenstein, Edward; Desplats, Paula; Ubhi, Kiren; Mante, Michael; Florio, Jazmin; Adame, Anthony; Winter, Stefan; Brandstaetter, Hemma; Meier, Dieter; Masliah, Eliezer

2015-07-01

Neural stem cells (NSCs) have been considered as potential therapy in Alzheimer's disease (AD) but their use is hampered by the poor survival of grafted cells. Supply of neurotrophic factors to the grafted cells has been proposed as a way to augment survival of the stem cells. In this context, we investigated the utility of Cerebrolysin (CBL), a peptidergic mixture with neurotrophic-like properties, as an adjunct to stem cell therapy in an APP transgenic (tg) model of AD. We grafted murine NSCs into the hippocampus of non-tg and APP tg that were treated systemically with CBL and analyzed after 1, 3, 6 and 9months post grafting. Compared to vehicle-treated non-tg mice, in the vehicle-treated APP tg mice there was considerable reduction in the survival of the grafted NSCs. Whereas, CBL treatment enhanced the survival of NSCs in both non-tg and APP tg with the majority of the surviving NSCs remaining as neuroblasts. The NSCs of the CBL treated mice displayed reduced numbers of caspase-3 and TUNEL positive cells and increased brain derived neurotrophic factor (BDNF) and furin immunoreactivity. These results suggest that CBL might protect grafted NSCs and as such be a potential adjuvant therapy when combined with grafting. Copyright © 2015. Published by Elsevier B.V.

Conditional Depletion of Hippocampal Brain-Derived Neurotrophic Factor Exacerbates Neuropathology in a Mouse Model of Alzheimer's Disease.

PubMed

Braun, David J; Kalinin, Sergey; Feinstein, Douglas L

2017-01-01

Damage occurring to noradrenergic neurons in the locus coeruleus (LC) contributes to the evolution of neuroinflammation and neurodegeneration in a variety of conditions and diseases. One cause of LC damage may be loss of neurotrophic support from LC target regions. We tested this hypothesis by conditional unilateral knockout of brain-derived neurotrophic factor (BDNF) in adult mice. To evaluate the consequences of BDNF loss in the context of neurodegeneration, the mice harbored familial mutations for human amyloid precursor protein and presenilin-1. In these mice, BDNF depletion reduced tyrosine hydroxylase staining, a marker of noradrenergic neurons, in the rostral LC. BDNF depletion also reduced noradrenergic innervation in the hippocampus, the frontal cortex, and molecular layer of the cerebellum, assessed by staining for dopamine beta hydroxylase. BDNF depletion led to an increase in cortical amyloid plaque numbers and size but was without effect on plaque numbers in the striatum, a site with minimal innervation from the LC. Interestingly, cortical Iba1 staining for microglia was reduced by BDNF depletion and was correlated with reduced dopamine beta hydroxylase staining. These data demonstrate that reduction of BDNF levels in an LC target region can cause retrograde damage to LC neurons, leading to exacerbation of neuropathology in distinct LC target areas. Methods to reduce BDNF loss or supplement BDNF levels may be of value to reduce neurodegenerative processes normally limited by LC noradrenergic activities.

Intranasal gene delivery for treating Parkinson's disease: overcoming the blood-brain barrier.

PubMed

Aly, Amirah E-E; Waszczak, Barbara L

2015-01-01

Developing a disease-modifying gene therapy for Parkinson's disease (PD) has been a high priority for over a decade. However, due to the inability of large biomolecules to cross the blood-brain barrier (BBB), the only means of delivery to the brain has been intracerebral infusion. Intranasal administration offers a non-surgical means of bypassing the BBB to deliver neurotrophic factors, and the genes encoding them, directly to the brain. This review summarizes: i) evidence demonstrating intranasal delivery to the brain of a number of biomolecules having therapeutic potential for various CNS disorders; and ii) evidence demonstrating neuroprotective efficacy of a subset of biomolecules specifically for PD. The intersection of these two spheres represents the area of opportunity for development of new intranasal gene therapies for PD. To that end, our laboratory showed that intranasal administration of glial cell line-derived neurotrophic factor (GDNF), or plasmid DNA nanoparticles encoding GDNF, provides neuroprotection in a rat model of PD, and that the cells transfected by the nanoparticle vector are likely to be pericytes. A number of genes encoding neurotrophic factors have therapeutic potential for PD, but few have been tested by the intranasal route and shown to be neuroprotective in a model of PD. Intranasal delivery provides a largely unexplored, promising approach for development of a non-invasive gene therapy for PD.

Functional regeneration of the transected recurrent laryngeal nerve using a collagen scaffold loaded with laminin and laminin-binding BDNF and GDNF

PubMed Central

Wang, Baoxin; Yuan, Junjie; Chen, Xinwei; Xu, Jiafeng; Li, Yu; Dong, Pin

2016-01-01

Recurrent laryngeal nerve (RLN) injury remains a challenge due to the lack of effective treatments. In this study, we established a new drug delivery system consisting of a tube of Heal-All Oral Cavity Repair Membrane loaded with laminin and neurotrophic factors and tested its ability to promote functional recovery following RLN injury. We created recombinant fusion proteins consisting of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) fused to laminin-binding domains (LBDs) in order to prevent neurotrophin diffusion. LBD-BDNF, LBD-GDNF, and laminin were injected into a collagen tube that was fitted to the ends of the transected RLN in rats. Functional recovery was assessed 4, 8, and 12 weeks after injury. Although vocal fold movement was not restored until 12 weeks after injury, animals treated with the collagen tube loaded with laminin, LBD-BDNF and LBD-GDNF showed improved recovery in vocalisation, arytenoid cartilage angles, compound muscle action potentials and regenerated fibre area compared to animals treated by autologous nerve grafting (p < 0.05). These results demonstrate the drug delivery system induced nerve regeneration following RLN transection that was superior to that induced by autologus nerve grafting. It may have potential applications in nerve regeneration of RLN transection injury. PMID:27558932

Adipose-derived stromal cells enhance auditory neuron survival in an animal model of sensory hearing loss.

PubMed

Schendzielorz, Philipp; Vollmer, Maike; Rak, Kristen; Wiegner, Armin; Nada, Nashwa; Radeloff, Katrin; Hagen, Rudolf; Radeloff, Andreas

2017-10-01

A cochlear implant (CI) is an electronic prosthesis that can partially restore speech perception capabilities. Optimum information transfer from the cochlea to the central auditory system requires a proper functioning auditory nerve (AN) that is electrically stimulated by the device. In deafness, the lack of neurotrophic support, normally provided by the sensory cells of the inner ear, however, leads to gradual degeneration of auditory neurons with undesirable consequences for CI performance. We evaluated the potential of adipose-derived stromal cells (ASCs) that are known to produce neurotrophic factors to prevent neural degeneration in sensory hearing loss. For this, co-cultures of ASCs with auditory neurons have been studied, and autologous ASC transplantation has been performed in a guinea pig model of gentamicin-induced sensory hearing loss. In vitro ASCs were neuroprotective and considerably increased the neuritogenesis of auditory neurons. In vivo transplantation of ASCs into the scala tympani resulted in an enhanced survival of auditory neurons. Specifically, peripheral AN processes that are assumed to be the optimal activation site for CI stimulation and that are particularly vulnerable to hair cell loss showed a significantly higher survival rate in ASC-treated ears. ASC transplantation into the inner ear may restore neurotrophic support in sensory hearing loss and may help to improve CI performance by enhanced AN survival. Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Long-term lithium treatment increases intracellular and extracellular brain-derived neurotrophic factor (BDNF) in cortical and hippocampal neurons at subtherapeutic concentrations.

PubMed

De-Paula, Vanessa J; Gattaz, Wagner F; Forlenza, Orestes V

2016-12-01

The putative neuroprotective effects of lithium treatment rely on the fact that it modulates several homeostatic mechanisms involved in the neurotrophic response, autophagy, oxidative stress, inflammation, and mitochondrial function. Lithium is a well-established therapeutic option for the acute and long-term management of bipolar disorder and major depression. The aim of this study was to evaluate the effects of subtherapeutic and therapeutic concentrations of chronic lithium treatment on brain-derived neurotrophic factor (BDNF) synthesis and secretion. Primary cultures of cortical and hippocampal neurons were treated with different subtherapeutic (0.02 and 0.2 mM) and therapeutic (2 mM) concentrations of chronic lithium treatment in cortical and hippocampal cell culture. Lithium treatment increased the intracellular protein expression of cortical neurons (10% at 0.02 mM) and hippocampal neurons (28% and 14% at 0.02 mM and 0.2 mM, respectively). Extracellular BDNF of cortical neurons increased 30% and 428% at 0.02 and 0.2 mM, respectively and in hippocampal neurons increased 44% at 0.02 mM. The present study indicates that chronic, low-dose lithium treatment up-regulates BDNF production in primary neuronal cell culture. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Blood Biomarkers Predict the Cognitive Effects of Aripiprazole in Patients with Acute Schizophrenia.

PubMed

Hori, Hikaru; Yoshimura, Reiji; Katsuki, Asuka; Atake, Kiyokazu; Igata, Ryohei; Konishi, Yuki; Beppu, Hiroki; Tominaga, Hirotaka

2017-03-06

Aripiprazole has been reported to exert variable effects on cognitive function in patients with schizophrenia. Therefore, in the present study, we evaluated biological markers, clinical data, and psychiatric symptoms in order to identify factors that influence cognitive function in patients with schizophrenia undergoing aripiprazole treatment. We evaluated cognitive function in 51 patients with schizophrenia using Brief Assessment of Cognition in Schizophrenia (BACS), as well as background information, psychiatric symptoms, plasma catecholamine metabolites-homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG)-, and serum brain-derived neurotrophic factor (BDNF). Multivariate analyses were performed in order to identify factors independently associated with cognitive function. Brain-derived neurotrophic factor levels, number of hospitalizations, and MHPG levels were associated with verbal memory and learning. Total hospitalization period and MHPG levels were associated with working memory. Age at first hospitalization and education were associated with motor speed. The number of hospital admissions, Positive and Negative Syndrome Scale negative subscale scores (PANSS-N), MHPG levels, BDNF levels, and Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) scores were associated with verbal fluency. Homovanillic acid and MHPG levels, duration of illness, and PANSS-N scores were associated with attention and processing speed. Brain-derived neurotrophic factor and MHPG levels were associated with executive function. These results suggest that treatment of psychiatric symptoms and cognitive dysfunction may be improved in patients treated with aripiprazole by controlling for these contributing factors.

Autism as a disorder of deficiency of brain-derived neurotrophic factor and altered metabolism of polyunsaturated fatty acids.

PubMed

Das, Undurti N

2013-10-01

Autism has a strong genetic and environmental basis in which inflammatory markers and factors concerned with synapse formation, nerve transmission, and information processing such as brain-derived neurotrophic factor (BDNF), polyunsaturated fatty acids (PUFAs): arachidonic (AA), eicosapentaenoic (EPA), and docosahexaenoic acids (DHA) and their products and neurotransmitters: dopamine, serotonin, acetylcholine, γ-aminobutyric acid, and catecholamines and cytokines are altered. Antioxidants, vitamins, minerals, and trace elements are needed for the normal metabolism of neurotrophic factors, eicosanoids, and neurotransmitters, supporting reports of their alterations in autism. But, the exact relationship among these factors and their interaction with genes and proteins concerned with brain development and growth is not clear. It is suggested that maternal infections and inflammation and adverse events during intrauterine growth of the fetus could lead to alterations in the gene expression profile and proteomics that results in dysfunction of the neuronal function and neurotransmitters, alteration(s) in the metabolism of PUFAs and their metabolites resulting in excess production of proinflammatory eicosanoids and cytokines and a deficiency of anti-inflammatory cytokines and bioactive lipids that ultimately results in the development of autism. Based on these evidences, it is proposed that selective delivery of BDNF and methods designed to augment the production of anti-inflammatory cytokines and eicosanoids and PUFAs may prevent, arrest, or reverse the autism disease process. Copyright © 2013 Elsevier Inc. All rights reserved.

Neurotrophic Factors NGF, GDNF and NTN Selectively Modulate HSV1 and HSV2 Lytic Infection and Reactivation in Primary Adult Sensory and Autonomic Neurons

PubMed Central

Yanez, Andy A.; Harrell, Telvin; Sriranganathan, Heather J.; Ives, Angela M.; Bertke, Andrea S.

2017-01-01

Herpes simplex viruses (HSV1 and HSV2) establish latency in peripheral ganglia after ocular or genital infection, and can reactivate to produce different patterns and frequencies of recurrent disease. Previous studies showed that nerve growth factor (NGF) maintains HSV1 latency in embryonic sympathetic and sensory neurons. However, adult sensory neurons are no longer dependent on NGF for survival, some populations cease expression of NGF receptors postnatally, and the viruses preferentially establish latency in different populations of sensory neurons responsive to other neurotrophic factors (NTFs). Thus, NGF may not maintain latency in adult sensory neurons. To identify NTFs important for maintaining HSV1 and HSV2 latency in adult neurons, we investigated acute and latently-infected primary adult sensory trigeminal (TG) and sympathetic superior cervical ganglia (SCG) after NTF removal. NGF and glial cell line-derived neurotrophic factor (GDNF) deprivation induced HSV1 reactivation in adult sympathetic neurons. In adult sensory neurons, however, neurturin (NTN) and GDNF deprivation induced HSV1 and HSV2 reactivation, respectively, while NGF deprivation had no effects. Furthermore, HSV1 and HSV2 preferentially reactivated from neurons expressing GFRα2 and GFRα1, the high affinity receptors for NTN and GDNF, respectively. Thus, NTN and GDNF play a critical role in selective maintenance of HSV1 and HSV2 latency in primary adult sensory neurons. PMID:28178213

Neurotrophic Factors NGF, GDNF and NTN Selectively Modulate HSV1 and HSV2 Lytic Infection and Reactivation in Primary Adult Sensory and Autonomic Neurons.

PubMed

Yanez, Andy A; Harrell, Telvin; Sriranganathan, Heather J; Ives, Angela M; Bertke, Andrea S

2017-02-07

Herpes simplex viruses (HSV1 and HSV2) establish latency in peripheral ganglia after ocular or genital infection, and can reactivate to produce different patterns and frequencies of recurrent disease. Previous studies showed that nerve growth factor (NGF) maintains HSV1 latency in embryonic sympathetic and sensory neurons. However, adult sensory neurons are no longer dependent on NGF for survival, some populations cease expression of NGF receptors postnatally, and the viruses preferentially establish latency in different populations of sensory neurons responsive to other neurotrophic factors (NTFs). Thus, NGF may not maintain latency in adult sensory neurons. To identify NTFs important for maintaining HSV1 and HSV2 latency in adult neurons, we investigated acute and latently-infected primary adult sensory trigeminal (TG) and sympathetic superior cervical ganglia (SCG) after NTF removal. NGF and glial cell line-derived neurotrophic factor (GDNF) deprivation induced HSV1 reactivation in adult sympathetic neurons. In adult sensory neurons, however, neurturin (NTN) and GDNF deprivation induced HSV1 and HSV2 reactivation, respectively, while NGF deprivation had no effects. Furthermore, HSV1 and HSV2 preferentially reactivated from neurons expressing GFRα2 and GFRα1, the high affinity receptors for NTN and GDNF, respectively. Thus, NTN and GDNF play a critical role in selective maintenance of HSV1 and HSV2 latency in primary adult sensory neurons.

Co-Ultramicronized Palmitoylethanolamide/Luteolin Promotes Neuronal Regeneration after Spinal Cord Injury

PubMed Central

Crupi, Rosalia; Impellizzeri, Daniela; Bruschetta, Giuseppe; Cordaro, Marika; Paterniti, Irene; Siracusa, Rosalba; Cuzzocrea, Salvatore; Esposito, Emanuela

2016-01-01

Spinal cord injury (SCI) stimulates activation of astrocytes and infiltration of immune cells at the lesion site; however, the mechanism that promotes the birth of new neurons is still under debate. Neuronal regeneration is restricted after spinal cord injury, but can be stimulated by experimental intervention. Previously we demonstrated that treatment co-ultramicronized palmitoylethanolamide and luteolin, namely co-ultraPEALut, reduced inflammation. The present study was designed to explore the neuroregenerative properties of co-ultraPEALut in an estabished murine model of SCI. A vascular clip was applied to the spinal cord dura at T5–T8 to provoke injury. Mice were treated with co-ultraPEALut (1 mg/kg, intraperitoneally) daily for 72 h after SCI. Co-ultraPEALut increased the numbers of both bromodeoxyuridine-positive nuclei and doublecortin-immunoreactive cells in the spinal cord of injured mice. To correlate neuronal development with synaptic plasticity a Golgi method was employed to analyze dendritic spine density. Co-ultraPEALut administration stimulated expression of the neurotrophic factors brain-derived neurotrophic factor, glial cell-derived neurotrophic factor, nerve growth factor, and neurotrophin-3. These findings show a prominent effect of co-ultraPEALut administration in the management of survival and differentiation of new neurons and spine maturation, and may represent a therapeutic treatment for spinal cord and other traumatic diseases. PMID:27014061

Reduced Cerebrospinal Fluid Levels of Brain-Derived Neurotrophic Factor Is Associated With Cognitive Impairment in Late-Life Major Depression

PubMed Central

Teixeira, Antonio L.; Machado-Vieira, Rodrigo; Talib, Leda L.; Radanovic, Marcia; Gattaz, Wagner F.; Forlenza, Orestes V.

2014-01-01

Objectives. Late-life depression (LLD) is associated with reduced neurotrophic support and abnormalities in neurodegenerative cascades. The aim of the present study is to determine the concentrations of brain-derived neurotrophic factor (BDNF), amyloid-β42, total Tau, and phosphorylated Tau in the cerebrospinal fluid (CSF) of patients with LLD and cognitive impairment compared to healthy older adults. Method. We included 25 antidepressant-free patients with LLD (10 with mild cognitive impairment [LLD + MCI] and 15 with no cognitive decline [LLD + NCD]) and 25 healthy older adults as a comparison group. Depressive symptoms were assessed by the 21-item Hamilton Depression Rating Scale (HDRS-21) and cognitive performance by a comprehensive cognitive battery. Results. Patients with LLD + MCI showed significantly lower CSF BDNF levels compared to LLD + NCD and healthy controls (p = .003). There were no significant differences in Alzheimer’s disease–related CSF biomarkers between groups. CSF BDNF concentrations were positively correlated with Cambridge Cognitive Test (CAMCOG) scores (r = .36, p = .02). Discussion. The present study adds to the growing body of evidence that abnormalities in the BDNF system are involved in the pathophysiology of LLD. The reduction of the availability of BDNF in the central nervous system may indicate increased vulnerability to the development of several age-related neuropsychiatric disorders as well as to adverse cognitive outcomes. PMID:25149921

Effects of Six-Week Ginkgo biloba Supplementation on Aerobic Performance, Blood Pro/Antioxidant Balance, and Serum Brain-Derived Neurotrophic Factor in Physically Active Men.

PubMed

Sadowska-Krępa, Ewa; Kłapcińska, Barbara; Pokora, Ilona; Domaszewski, Przemysław; Kempa, Katarzyna; Podgórski, Tomasz

2017-07-26

Extracts of Ginkgo biloba leaves, a natural source of flavonoids and polyphenolic compounds, are commonly used as therapeutic agents for the improvement of both cognitive and physiological performance. The present study was aimed to test the effects of a six-week supplementation with 160 mg/day of a standardized extract of Ginkgo biloba or a matching placebo on aerobic performance, blood antioxidant capacity, and brain-derived neurotrophic factor (BDNF) level in healthy, physically active young men, randomly allocated to two groups ( n = 9 each). At baseline, as well as on the day following the treatment, the participants performed an incremental cycling test for the assessment of maximal oxygen uptake. Venous blood samples taken at rest, then immediately post-test and following 1 h of recovery, were analyzed for activities of antioxidant enzymes and plasma concentrations of non-enzymatic antioxidants, total phenolics, uric acid, lipid peroxidation products, ferric reducing ability of plasma (FRAP), and serum brain-derived neurotrophic factor (BDNF). Our results show that six weeks' supplementation with Ginkgo biloba extract in physically active young men may provide some marginal improvements in their endurance performance expressed as VO₂max and blood antioxidant capacity, as evidenced by specific biomarkers, and elicit somewhat better neuroprotection through increased exercise-induced production of BDNF.

Striatal increase of neurotrophic factors as a mechanism of nicotine protection in experimental parkinsonism.

PubMed

Maggio, R; Riva, M; Vaglini, F; Fornai, F; Racagni, G; Corsini, G U

1997-01-01

The repeated finding of an apparent protective effect of cigarette smoking on the risk of Parkinson's disease is one of the few consistent results in the epidemiology of this disorder. Among the innumerous substances that originate from tobacco smoke, nicotine is by far the most widely studied, and the most likely candidate for a protective effect against neuronal degeneration in Parkinson's disease. Nicotine is a natural alkaloid that has considerable stimulatory effects on the central nervous system (CNS). Its effects on the CNS are mediated by the activation of neuronal heteromeric acetylcholine-gated ion channel receptors (nAChR, also termed nicotinic acetylcholine receptors). In the present study, we describe the neuroprotective effects of (-)nicotine in two animal models of parkinsonism: the diethyldithiocarbamate (DDC)-induced enhancement of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity in mice, and the methamphetamine-induced neurotoxicity in rats and mice. In parallel experiments, we found that (-)nicotine induces the basic fibroblast growth factor (FGF-2) and the brain-derived neurotrophic factor (BDNF) in rat striatum. As FGF-2 and BDNF have been reported to be neuroprotective for dopaminergic cells, our data indicate that the increase in neurotrophic factors is a possible mechanism by which (-)nicotine protects from experimental parkinsonisms. Moreover, they suggest that nAChR agonists could be of potential benefit in the progression of Parkinson's disease.

Prevention of Memory Impairment and Neurotrophic Factors Increased by Lithium in Wistar Rats Submitted to Pneumococcal Meningitis Model

PubMed Central

Simões, Lutiana R.; Abreu, Roberta R. E. S.; Goularte, Jéssica A.; Collodel, Allan; Giridharan, Vijayasree Vayalanellore

2017-01-01

The aim of this study was to investigate the effects of lithium on brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and glial cell line-derived neurotrophic factor (GDNF) expression in the hippocampus and on memory in experimental pneumococcal meningitis. The mood-stabilizer lithium is known as a neuroprotective agent with many effects on the brain. In this study, animals received either artificial cerebrospinal fluid or Streptococcus pneumoniae suspension at a concentration of 5 × 109 CFU/mL. Eighteen hours after induction, all animals received ceftriaxone. The animals received saline or lithium (47.5 mg/kg) or tamoxifen (1 mg/kg) as adjuvant treatment, and they were separated into six groups: control/saline, control/lithium, control/tamoxifen, meningitis/saline, meningitis/lithium, and meningitis/tamoxifen. Ten days after meningitis induction, animals were subjected to open-field habituation and the step-down inhibitory avoidance tasks. Immediately after these tasks, the animals were killed and their hippocampus was removed to evaluate the expression of BDNF, NGF, and GDNF. In the meningitis group, treatment with lithium and tamoxifen resulted in improvement in memory. Meningitis group showed decreased expression of BDNF and GDNF in the hippocampus while lithium reestablished the neurotrophin expression. Lithium was able to prevent memory impairment and reestablishes hippocampal neurotrophin expression in experimental pneumococcal meningitis. PMID:29200666

Extinction-induced "despair" in aged and adult rats: links to neurotrophins in frontal cortex and hippocampus.

PubMed

Topic, Bianca; Huston, Joseph P; Namestkova, Katerina; Zhu, Shun-Wei; Mohammed, Abdul H; Schulz, Daniela

2008-10-01

In the search for animal models of human geriatric depression, we found that operant extinction of escape from water results in the expression of immobility in different age groups, indicative of behavioral "despair", which was also associated with the resistance-to-extinction (RTE) expressed by these animals. With respect to the neurotrophin hypothesis of depression, nerve-growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) protein levels in frontal cortex (FC) and hippocampus (HP) were examined and related to behavioral immobility and RTE in the water maze in aged and adult Wistar rats. Age-related increases in levels of NGF were found in HP and of NT-3 in FC. Indices of immobility showed relationships in the aged with NGF and, in adults, with BDNF, pointing to a dissociation of neurotrophic involvement in extinction trial-induced "despair" in aged and adult rats. The present results support the hypothesis, that extinction-induced immobility in the water maze reflects a state akin to behavioral despair and point to age-related differences of neurotrophic involvement in depressive-like symptoms. The concept of extinction-induced behavioral "despair" in the aged subsumes several aspects of human geriatric depression, such as co-morbidity of learning impairment and anxiety, and, thus could represent a useful paradigm to examine the neuronal mechanisms underlying depression, especially in aged rodents.

Trunk-pelvis coordination during turning: A cross sectional study of young adults with and without a history of low back pain.

PubMed

Smith, Jo Armour; Kulig, Kornelia

2016-07-01

During steady-state locomotion, symptomatic individuals with low back pain demonstrate reduced ability to modulate coordination between the trunk and the pelvis in the axial plane. It is unclear if this is also true during functional locomotor perturbations such as changing direction, or if this change in coordination adaptability persists between symptomatic episodes. The purpose of this study was to compare trunk-pelvis coordination during walking turns in healthy individuals and asymptomatic individuals with a history of low back pain. Participants performed multiple ipsilateral turns. Axial plane inter-segmental coordination and stride-to-stride coordination variability were quantified using the vector coding technique. Frequency of coordination mode and amplitude of coordination variability was compared between groups using Wilcoxon signed-rank tests and paired t-tests respectively. During stance phase of the turn, there was no significant difference in either inter-segmental coordination or coordination variability between groups. Inter-segmental coordination between the trunk and the pelvis was predominantly inphase during this part of the turn. During swing phase, patterns of coordination were more diversified, and individuals with a history of low back pain had significantly greater trunk phase coordination than healthy controls. Coordination variability was the same in both groups. Changes in trunk-pelvis coordination are evident between symptomatic episodes in individuals with a history of low back pain. However, previously demonstrated decreases in coordination variability were not found between symptomatic episodes in individuals with recurrent low back pain and therefore may represent a response to concurrent pain rather than a persistent change in motor control. Copyright © 2016 Elsevier Ltd. All rights reserved.

Describing care coordination of gynecologic oncology in western healthcare settings: a rapid review.

PubMed

Grant, Sean; Motala, Aneesa; Chrystal, Joya G; Shanman, Roberta; Zuchowski, Jessica; Zephyrin, Laurie; Cordasco, Kristina M

2018-05-23

Caring for women with gynecologic malignancies requires multidisciplinary communication and coordination across multiple providers. This article discusses a rapid review of the literature on characteristics of care coordination for gynecologic malignancies. Five electronic databases (from inception through March 2015) were searched for empirical studies on coordinated care models for female adults with gynecologic malignancies. A single reviewer extracted and synthesized information on how care was coordinated, how care teams made decisions, who performed what tasks, how care teams communicated information to coordinate care, and potential impact of the characteristic on delivering coordinated care. From 26 included studies, predominant characteristics of coordinated care were identified: multidisciplinary teams, patient navigators, scheduled follow-ups, survivorship care plans, and colocated services. Decision-making was best documented for studies that utilized teams that had periodic scheduled meetings with set agendas and consistent procedures. Providers' roles in coordinating care were numerous, reflecting professional backgrounds: oncologists had most authority in making treatment decisions; radiologists and pathologists shared vital biomedical information; and nurses coordinated care and communicated with patients. Communication tools and strategies across studies included having shared medical records, integrated treatment plans, and telephone-based or teleconferencing communication. There was limited information available on the impact of characteristics and accompanying strategies or tools. Several characteristics of care coordination models for gynecologic cancers have been published in the literature. Further investigation is needed to understand the relative effectiveness of these ways to coordinate care.

Networking Multiple Autonomous Air and Ocean Vehicles for Oceanographic Research and Monitoring

NASA Astrophysics Data System (ADS)

McGillivary, P. A.; Borges de Sousa, J.; Rajan, K.

2013-12-01

Autonomous underwater and surface vessels (AUVs and ASVs) are coming into wider use as components of oceanographic research, including ocean observing systems. Unmanned airborne vehicles (UAVs) are now available at modest cost, allowing multiple UAVs to be deployed with multiple AUVs and ASVs. For optimal use good communication and coordination among vehicles is essential. We report on the use of multiple AUVs networked in communication with multiple UAVs. The UAVs are augmented by inferential reasoning software developed at MBARI that allows UAVs to recognize oceanographic fronts and change their navigation and control. This in turn allows UAVs to automatically to map frontal features, as well as to direct AUVs and ASVs to proceed to such features and conduct sampling via onboard sensors to provide validation for airborne mapping. ASVs can also act as data nodes for communication between UAVs and AUVs, as well as collecting data from onboard sensors, while AUVs can sample the water column vertically. This allows more accurate estimation of phytoplankton biomass and productivity, and can be used in conjunction with UAV sampling to determine air-sea flux of gases (e.g. CO2, CH4, DMS) affecting carbon budgets and atmospheric composition. In particular we describe tests in July 2013 conducted off Sesimbra, Portugal in conjunction with the Portuguese Navy by the University of Porto and MBARI with the goal of tracking large fish in the upper water column with coordinated air/surface/underwater measurements. A thermal gradient was observed in the infrared by a low flying UAV, which was used to dispatch an AUV to obtain ground truth to demonstrate the event-response capabilities using such autonomous platforms. Additional field studies in the future will facilitate integration of multiple unmanned systems into research vessel operations. The strength of hardware and software tools described in this study is to permit fundamental oceanographic measurements of both ocean and atmosphere over temporal and spatial scales that have previously been problematic. The methods demonstrated are particularly suited to the study of oceanographic fronts and for tracking and mapping oil spills or plankton blooms. With the networked coordination of multiple autonomous systems, individual components may be changed out while ocean observations continue, allowing coarse to fine spatial studies of hydrographic features over temporal dimensions that would otherwise be difficult, including diurnal and tidal periods. Constraints on these methods currently involve coordination of data archiving systems into shipboard operating systems, familiarization of oceanographers with these methods, and existing nearshore airspace use constraints on UAVs. An important outcome of these efforts is to understand the methodology for using multiple heterogeneous autonomous vehicles for targeted science exploration.

Effect of glucagon-like peptide-1 analogue; Exendin-4, on cognitive functions in type 2 diabetes mellitus; possible modulation of brain derived neurotrophic factor and brain Visfatin.

PubMed

Abdelwahed, O M; Tork, O M; Gamal El Din, M M; Rashed, L; Zickri, M

2018-05-01

Brain derived neurotrophic factor (BDNF) is one of the most essential neurotrophic factors in the brain. BDNF is involved in learning, memory and locomotion suggesting it as a target in type 2 diabetes mellitus (T2DM) associated cognitive changes. Visfatin; an adipokine discovered to be expressed in the brain; was found to have multiple effects including its participation in keeping energy supply to the cell and is consequentially involved in cell survival. Its role in cognitive functions in T2DM was not studied before. Recent studies point to the possible neuro-protective mechanisms of glucagon-like peptide 1 analogue: Exendin-4 (Ex-4) in many cognitive disorders, but whether BDNF or Visfatin are involved or not in its neuro-protective mechanisms; is still unknown. to study the changes in cognitive functions in T2DM, either not treated or treated with Glucagon-like peptide 1 (GLP-1) analogue: Ex-4, and to identify the possible underlying mechanisms of these changes and whether BDNF and brain Visfatin are involved. A total of 36 adult male wistar albino rats were divided into 4 groups; Control, Exendin-4 control, Diabetic and Exendin-4 treated groups. At the end of the study, Y-maze and open field tests were done the day before scarification to assess spatial working memory and locomotion, respectively. Fasting glucose and insulin, lipid profile and tumor necrosis factor- alpha (TNF-α) were measured in the serum. Homeostasis model assessment insulin resistance was calculated. In the brain tissue, malondialdehyde (MDA) level, gene expression and protein levels of BDNF and Visfatin, area of degenerated neurons, area of glial cells and area % of synaptophysin immunoexpression were assessed. Compared with the control, the untreated diabetic rats showed insulin resistance, dyslipidemia and elevation of serum TNF-α. The brain tissue showed down-regulation of BDNF gene expression and reduction of its protein level, up-regulation of Visfatin gene expression and elevation of its protein level, increase in MDA, area of degenerated neurons and area of glial cells and reduction in area % of synaptophysin immunoexpression. These changes were paralleled with significant deterioration in spatial working memory and locomotion. Treatment of diabetic rats with Ex-4 reversed all these changes. T2DM has a negative impact on cognitive functions through different pathological and subcellular mechanisms. The current study provides evidence for involvement of BDNF and brain Visfatin in T2DM- associated cognitive dysfunction. BDNF and brain Visfatin were also found to contribute to the neuro-protective effect of Ex-4 via modulation of inflammation, oxidative stress, neuro-degeneration and synaptic function. Copyright © 2018 Elsevier Inc. All rights reserved.

BNDF heterozygosity is associated with memory deficits and alterations in cortical and hippocampal EEG power.

PubMed

Geist, Phillip A; Dulka, Brooke N; Barnes, Abigail; Totty, Michael; Datta, Subimal

2017-08-14

Brain derived neurotrophic factor (BDNF) plays a pivotal role in structural plasticity, learning, and memory. Electroencephalogram (EEG) spectral power in the cortex and hippocampus has also been correlated with learning and memory. In this study, we investigated the effect of globally reduced BDNF levels on learning behavior and EEG power via BDNF heterozygous (KO) rats. We employed several behavioral tests that are thought to depend on cortical and hippocampal plasticity to varying degrees: novel object recognition, a test that is reliant on a variety of cognitive systems; contextual fear, which is highly hippocampal-dependent; and cued fear, which has been shown to be amygdala-dependent. We also examined the effects of BDNF reduction on cortical and hippocampal EEG spectral power via chronically implanted electrodes in the motor cortex and dorsal hippocampus. We found that BDNF KO rats were impaired in novelty recognition and fear memory retention, while hippocampal EEG power was decreased in slow waves and increased in fast waves. Interestingly, our results, for the first time, show sexual dimorphism in each of our tests. These results support the hypothesis that BDNF drives both cognitive plasticity and coordinates EEG activity patterns, potentially serving as a link between the two. Copyright © 2017 Elsevier B.V. All rights reserved.

Female gender and gastrointestinal symptoms, not brain-derived neurotrophic factor, are associated with depression and anxiety in cirrhosis.

PubMed

Xu, Hong; Zhou, Yang; Ko, Fangyuan; Ping, Jian; Zhang, Jing; Zhao, Changqing; Xu, Lieming

2017-03-01

Cirrhosis places a substantial burden on the psychological status of affected individuals. The aim of our study was to identify the associated factors of psychological distress in cirrhosis. A total of 208 patients with cirrhosis were recruited. Each patient received validated questionnaires to assess gastrointestinal (GI) symptoms, depression, and anxiety. Serum brain-derived neurotrophic factor (BDNF) levels were measured by enzyme-linked immunosorbent assay. A total of 16.35% of patients (n = 34) were diagnosed with depression and 10.58% (n = 22) with anxiety. The percentages of female patients among those diagnosed with depression and anxiety were 58.8% and 77.3%, respectively, which were significantly higher than that in non-depressed (35.1%) and non-anxious patients (34.4%). The patients who showed more GI symptoms had higher depression and anxiety scores. The GI symptom scores of patients with depression and anxiety were 4 (2.75, 7) and 4 (2.75, 7.25), respectively, which were significantly higher than that of patients without depression (2 [0, 4]) and anxiety (2 [1, 4]). Significantly higher depression and anxiety scores were detected in patients who suffered from abdominal bloating, belching, anorexia, abdominal pain, nausea/vomiting, and constipation. Cirrhotic patients had higher serum levels of BDNF than healthy controls (159.33 [96.64, 243.30] pg/mL vs. 70.74 [56.58, 93.52] pg/mL). In the cirrhosis group, there was no significant difference in BDNF levels between depressed and non-depressed patients. Multiple linear regression analysis revealed that depression and anxiety were each independently associated with female gender and GI symptom scores. Female gender and GI symptoms are closely associated with depression and anxiety in cirrhosis. There is no significant correlation between BDNF level and psychological distress in cirrhosis. © 2016 The Japan Society of Hepatology.

The Impact of Aerobic Exercise on Brain-Derived Neurotrophic Factor and Neurocognition in Individuals With Schizophrenia: A Single-Blind, Randomized Clinical Trial.

PubMed

Kimhy, David; Vakhrusheva, Julia; Bartels, Matthew N; Armstrong, Hilary F; Ballon, Jacob S; Khan, Samira; Chang, Rachel W; Hansen, Marie C; Ayanruoh, Lindsey; Lister, Amanda; Castrén, Eero; Smith, Edward E; Sloan, Richard P

2015-07-01

Individuals with schizophrenia display substantial neurocognitive deficits for which available treatments offer only limited benefits. Yet, findings from studies of animals, clinical and nonclinical populations have linked neurocognitive improvements to increases in aerobic fitness (AF) via aerobic exercise training (AE). Such improvements have been attributed to up-regulation of brain-derived neurotrophic factor (BDNF). However, the impact of AE on neurocognition, and the putative role of BDNF, have not been investigated in schizophrenia. Employing a proof-of-concept, single-blind, randomized clinical trial design, 33 individuals with schizophrenia were randomized to receive standard psychiatric treatment (n = 17; "treatment as usual"; TAU) or attend a 12-week AE program (n = 16) utilizing active-play video games (Xbox 360 Kinect) and traditional AE equipment. Participants completed assessments of AF (indexed by VO2 peak ml/kg/min), neurocognition (MATRICS Consensus Cognitive Battery), and serum-BDNF before and after and 12-week period. Twenty-six participants (79%) completed the study. At follow-up, the AE participants improved their AF by 18.0% vs a -0.5% decline in the TAU group (P = .002) and improved their neurocognition by 15.1% vs -2.0% decline in the TAU group (P = .031). Hierarchical multiple regression analyses indicated that enhancement in AF and increases in BDNF predicted 25.4% and 14.6% of the neurocognitive improvement variance, respectively. The results indicate AE is effective in enhancing neurocognitive functioning in people with schizophrenia and provide preliminary support for the impact of AE-related BDNF up-regulation on neurocognition in this population. Poor AF represents a modifiable risk factor for neurocognitive dysfunction in schizophrenia for which AE training offer a safe, nonstigmatizing, and side-effect-free intervention. © The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

The Brain-Derived Neurotrophic Factor Val66Met Polymorphism, Delivery Method, Birth Weight, and Night Sleep Duration as Determinants of Obesity in Vietnamese Children of Primary School Age.

PubMed

Tuyet, Le Thi; Nhung, Bui Thi; Dao, Duong Thi Anh; Hanh, Nguyen Thi Hong; Tuyen, Le Danh; Binh, Tran Quang; Thuc, Vu Thi Minh

2017-10-01

Obesity is a complex disease that involves both environmental and genetic factors in its pathogenesis. Several studies have identified multiple obesity-associated loci in many populations. However, their contribution to obesity in the Vietnamese population is not fully described, especially in children. The study aimed to investigate the association of obesity with Val66Met polymorphism in brain-derived neurotrophic factor (BDNF) gene, delivery method, birth weight, and lifestyle factors in Vietnamese primary school children. A case-control study was conducted on 559 children aged 6-11 years (278 obese cases and 281 normal controls). The obesity of the children was classified using both criteria of International Obesity Task Force (IOTF, 2000) and World Health Organization (WHO, 2007). Lifestyle factors, birth delivery, and birth weight of the children were self-reported by parents. The BDNF genotype was analyzed using the polymerase chain reaction-restriction fragment length polymorphism method. Association was evaluated by multivariate logistic regression and cross-validated by the Bayesian model averaging method. The most significantly independent factors for obesity were delivery method (cesarean section vs. vaginal delivery, β = 0.56, p = 0.007), birth weight (>3500 to <4000 g vs. 2500-3500 g, β = 0.52, p = 0.035; ≥4000 g vs. 2500-3500 g, β = 1.06, p = 0.015), night sleep duration (<8 h/day vs. ≥8 h/day, β = 0.99, p < 0.0001), and BDNF Val66Met polymorphism (AA and GG vs. AG, β = 0.38, p = 0.039). The study suggested the significant association of delivery method, birth weight, night sleep duration, and BDNF Val66Met polymorphism, with obesity in Vietnamese primary school children.

Neuroprotective potential of high-dose biotin.

PubMed

McCarty, Mark F; DiNicolantonio, James J

2017-11-01

A recent controlled trial has established that high-dose biotin supplementation - 100 mg, three times daily - has a stabilizing effect on progression of multiple sclerosis (MS). Although this effect has been attributed to an optimization of biotin's essential cofactor role in the brain, a case can be made that direct stimulation of soluble guanylate cyclase (sGC) by pharmacological concentrations of biotin plays a key role in this regard. The utility of high-dose biotin in MS might reflect an anti-inflammatory effect of cGMP on the cerebral microvasculature, as well on oligodendrocyte differentiation and on Schwann cell production of neurotrophic factors thought to have potential for managing MS. But biotin's ability to boost cGMP synthesis in the brain may have broader neuroprotective potential. In many types of neurons and neural cells, cGMP exerts neurotrophic-mimetic effects - entailing activation of the PI3K-Akt and Ras-ERK pathways - that promote neuron survival and plasticity. Hippocampal long term potentiation requires nitric oxide synthesis, which in turn promotes an activating phosphorylation of CREB via a pathway involving cGMP and protein kinase G (PKG). In Alzheimer's disease (AD), amyloid beta suppresses this mechanism by inhibiting sGC activity; agents which exert a countervailing effect by boosting cGMP levels tend to restore effective long-term potentiation in rodent models of AD. Moreover, NO/cGMP suppresses amyloid beta production within the brain by inhibiting expression of amyloid precursor protein and BACE1. In conjunction with cGMP's ability to oppose neuron apoptosis, these effects suggest that high-dose biotin might have potential for the prevention and management of AD. cGMP also promotes neurogenesis, and may lessen stroke risk by impeding atherogenesis and hypertrophic remodeling in the cerebral vasculature. The neuroprotective potential of high-dose biotin likely could be boosted by concurrent administration of brain-permeable phosphodiesterase-5 inhibitors. Copyright © 2017 Elsevier Ltd. All rights reserved.

CASPT2 study of inverse sandwich-type dinuclear Cr(I) and Fe(I) complexes of the dinitrogen molecule: significant differences in spin multiplicity and coordination structure between these two complexes.

PubMed

Nakagaki, Masayuki; Sakaki, Shigeyoshi

2014-02-20

Inverse sandwich-type complexes (ISTCs), (μ-N2)[M(AIP)]2 (AIPH = (Z)-1-amino-3-imino-prop-1-ene; M = Cr and Fe), were investigated with the CASPT2 method. In the ISTC of Cr, the ground state takes a singlet spin multiplicity. However, the singlet to nonet spin states are close in energy to each other. The thermal average of effective magnetic moments (μeff) of these spin multiplicities is close to the experimental value. The η(2)-side-on coordination structure of N2 is calculated to be more stable than the η(1)-end-on coordination one. This is because the d-orbital of Cr forms a strong dπ-π* bonding interaction with the π* orbital of N2 in molecular plane. In the ISTC of Fe, on the other hand, the ground state takes a septet spin multiplicity, which agrees well with the experimentally reported μeff value. The η(1)-end-on structure of N2 is more stable than the η(2)-side-on structure. In the η(1)-end-on structure, two doubly occupied d-orbitals of Fe can form two dπ-π* bonding interactions. The negative spin density is found on the bridging N2 ligand in the Fe complex but is not in the Cr complex. All these interesting differences between ISTCs of Cr and Fe are discussed on the basis of the electronic structure and bonding nature.

Microbial keratitis secondary to unintended poor compliance with scleral gas-permeable contact lenses.

PubMed

Zimmerman, Aaron B; Marks, Amanda

2014-01-01

To report a case of neurotrophic keratitis in which scleral contact lenses improved vision from 20/100 to 20/20, however, due to poor lens care, an incident of microbial keratitis developed. A 64-year-old man with an ocular history of neurotrophic keratitis secondary to herpes simplex in each eye was successfully fit with scleral lenses. He subsequently developed microbial keratitis due to a number of risk factors. The lesion was culture negative, yet was very responsive to treatment with moxifloxacin. The lesion fully healed, and the patient did not suffer additional vision loss. This case demonstrates the ability of scleral lenses to correct visual impairments secondary to poor epithelial integrity and illustrates the importance of the practitioner providing detailed lens care instruction.

Brain-derived neurotrophic factor in the nucleus tractus solitarii modulates glucose homeostasis after carotid chemoreceptor stimulation in rats.

PubMed

Montero, Sergio; Cuéllar, Ricardo; Lemus, Mónica; Avalos, Reyes; Ramírez, Gladys; de Álvarez-Buylla, Elena Roces

2012-01-01

Neuronal systems, which regulate energy intake, energy expenditure and endogenous glucose production, sense and respond to input from hormonal related signals that convey information from body energy availability. Carotid chemoreceptors (CChr) function as sensors for circulating glucose levels and contribute to glycemic counterregulatory responses. Brain-derived neurotrophic factor (BDNF) that plays an important role in the endocrine system to regulate glucose metabolism could play a role in hyperglycemic glucose reflex with brain glucose retention (BGR) evoked by anoxic CChr stimulation. Infusing BDNF into the nucleus tractus solitarii (NTS) before CChr stimulation, showed that this neurotrophin increased arterial glucose and BGR. In contrast, BDNF receptor (TrkB) antagonist (K252a) infusions in NTS resulted in a decrease in both glucose variables.

Bioengineered nerve regeneration and muscle reinnervation

PubMed Central

Kingham, Paul J; Terenghi, Giorgio

2006-01-01

The peripheral nervous system has the intrinsic capacity to regenerate but the reinnervation of muscles is often suboptimal and results in limited recovery of function. Injuries to nerves that innervate complex organs such as the larynx are particularly difficult to treat. The many functions of the larynx have evolved through the intricate neural regulation of highly specialized laryngeal muscles. In this review, we examine the responses of nerves and muscles to injury, focusing on changes in the expression of neurotrophic factors, and highlight differences between the skeletal limb and laryngeal muscle systems. We also describe how artificial nerve conduits have become a useful tool for delivery of neurotrophic factors as therapeutic agents to promote peripheral nerve repair and might eventually be useful in the treatment of laryngeal nerve injury. PMID:17005023

Advances and Future Applications of Augmented Peripheral Nerve Regeneration

PubMed Central

Jones, Salazar; Eisenberg, Howard M.; Jia, Xiaofeng

2016-01-01

Peripheral nerve injuries remain a significant source of long lasting morbidity, disability, and economic costs. Much research continues to be performed in areas related to improving the surgical outcomes of peripheral nerve repair. In this review, the physiology of peripheral nerve regeneration and the multitude of efforts to improve surgical outcomes are discussed. Improvements in tissue engineering that have allowed for the use of synthetic conduits seeded with neurotrophic factors are highlighted. Selected pre-clinical and available clinical data using cell based methods such as Schwann cell, undifferentiated, and differentiated stem cell transplantation to guide and enhance peripheral nerve regeneration are presented. The limitations that still exist in the utility of neurotrophic factors and cell-based therapies are outlined. Strategies that are most promising for translation into the clinical arena are suggested. PMID:27618010

Serum concentrations of brain-derived neurotrophic factor in patients with gender identity disorder.

PubMed

Fontanari, Anna-Martha V; Andreazza, Tahiana; Costa, Ângelo B; Salvador, Jaqueline; Koff, Walter J; Aguiar, Bianca; Ferrari, Pamela; Massuda, Raffael; Pedrini, Mariana; Silveira, Esalba; Belmonte-de-Abreu, Paulo S; Gama, Clarissa S; Kauer-Sant'Anna, Marcia; Kapczinski, Flavio; Lobato, Maria Ines R

2013-10-01

Gender Identity Disorder (GID) is characterized by a strong and persistent cross-gender identification that affects different aspects of behavior. Brain-derived neurotrophic factor (BDNF) plays a critical role in neurodevelopment and neuroplasticity. Altered BDNF-signaling is thought to contribute to the pathogenesis of psychiatric disordersand is related to traumatic life events. To examine serum BDNF levels, we compared one group of DSM-IV GID patients (n = 45) and one healthy control group (n = 66). Serum BDNF levels were significantly decreased in GID patients (p = 0.013). This data support the hypothesis that the reduction found in serum BDNF levels in GID patients may be related to the psychological abuse that transsexuals are exposed during their life. Copyright © 2013 Elsevier Ltd. All rights reserved.

Brain-Derived Neurotrophic Factor Serum Levels and Hippocampal Volume in Mild Cognitive Impairment and Dementia due to Alzheimer Disease.

PubMed

Borba, Ericksen Mielle; Duarte, Juliana Avila; Bristot, Giovana; Scotton, Ellen; Camozzato, Ana Luiza; Chaves, Márcia Lorena Fagundes

2016-01-01

Hippocampal atrophy is a recognized biomarker of Alzheimer disease (AD) pathology. Serum brain-derived neurotrophic factor (BDNF) reduction has been associated with neurodegeneration. We aimed to evaluate BDNF serum levels and hippocampal volume in clinical AD (dementia and mild cognitive impairment [MCI]). Participants were 10 patients with MCI and 13 with dementia due to AD as well as 10 healthy controls. BDNF serum levels were determined by ELISA and volumetric measures with NeuroQuant®. MCI and dementia patients presented lower BDNF serum levels than healthy participants; dementia patients presented a smaller hippocampal volume than MCI patients and healthy participants. The findings support that the decrease in BDNF might start before the establishment of neuronal injury expressed by the hippocampal reduction.

Numerical solution of potential flow about arbitrary 2-dimensional multiple bodies

NASA Technical Reports Server (NTRS)

Thompson, J. F.; Thames, F. C.

1982-01-01

A procedure for the finite-difference numerical solution of the lifting potential flow about any number of arbitrarily shaped bodies is given. The solution is based on a technique of automatic numerical generation of a curvilinear coordinate system having coordinate lines coincident with the contours of all bodies in the field, regardless of their shapes and number. The effects of all numerical parameters involved are analyzed and appropriate values are recommended. Comparisons with analytic solutions for single Karman-Trefftz airfoils and a circular cylinder pair show excellent agreement. The technique of application of the boundary-fitted coordinate systems to the numerical solution of partial differential equations is illustrated.

A distributed data base management facility for the CAD/CAM environment

NASA Technical Reports Server (NTRS)

Balza, R. M.; Beaudet, R. W.; Johnson, H. R.

1984-01-01

Current/PAD research in the area of distributed data base management considers facilities for supporting CAD/CAM data management in a heterogeneous network of computers encompassing multiple data base managers supporting a variety of data models. These facilities include coordinated execution of multiple DBMSs to provide for administration of and access to data distributed across them.

Jigsaw Research Communities: Coordinating Research and Service across Multiple Courses to Serve a Single Community Partner

ERIC Educational Resources Information Center

Cross, Anne; Eckberg, Deborah A.

2015-01-01

This article describes a public scholarship project in which two faculty members worked together to integrate service-learning and research into multiple courses to benefit a single community partner. The project linked undergraduate students, graduate students, and faculty in a broad-based research endeavor that contributed to the survival and…

Stoichiometric control of multiple different tectons in coordination-driven self-assembly: preparation of fused metallacyclic polygons.

PubMed

Lee, Junseong; Ghosh, Koushik; Stang, Peter J

2009-09-02

We present a general strategy for the synthesis of stable, multicomponent fused polygon complexes in which coordination-driven self-assembly allows for single supramolecular species to be formed from multicomponent self-assembly and the shape of the obtained polygons can be controlled simply by changing the ratio of individual components. The compounds have been characterized by multinuclear NMR spectroscopy and electrospray ionization mass spectrometry.

Students with Disabilities: Better Federal Coordination Could Lessen Challenges in the Transition from High School. Report to the Ranking Member, Committee on Education and the Workforce, House of Representatives. GAO-12-594

ERIC Educational Resources Information Center

Moran, Revae E.

2012-01-01

The transition out of high school to postsecondary education or the workforce can be a challenging time, especially for students with disabilities. Multiple federal agencies fund programs to support these students during their transition. In 2003, GAO reported that limited coordination among these programs can hinder a successful transition. GAO…

Adaptive method with intercessory feedback control for an intelligent agent

DOEpatents

Goldsmith, Steven Y.

2004-06-22

An adaptive architecture method with feedback control for an intelligent agent provides for adaptively integrating reflexive and deliberative responses to a stimulus according to a goal. An adaptive architecture method with feedback control for multiple intelligent agents provides for coordinating and adaptively integrating reflexive and deliberative responses to a stimulus according to a goal. Re-programming of the adaptive architecture is through a nexus which coordinates reflexive and deliberator components.

In vitro efficacy of a gene-activated nerve guidance conduit incorporating non-viral PEI-pDNA nanoparticles carrying genes encoding for NGF, GDNF and c-Jun.

PubMed

Lackington, William A; Raftery, Rosanne M; O'Brien, Fergal J

2018-06-07

Despite the success of tissue engineered nerve guidance conduits (NGCs) for the treatment of small peripheral nerve injuries, autografts remain the clinical gold standard for larger injuries. The delivery of neurotrophic factors from conduits might enhance repair for more effective treatment of larger injuries but the efficacy of such systems is dependent on a safe, effective platform for controlled and localised therapeutic delivery. Gene therapy might offer an innovative approach to control the timing, release and level of neurotrophic factor production by directing cells to transiently sustain therapeutic protein production in situ. In this study, a gene-activated NGC was developed by incorporating non-viral polyethyleneimine-plasmid DNA (PEI-pDNA) nanoparticles (N/P 7 ratio, 2μg dose) with the pDNA encoding for nerve growth factor (NGF), glial derived neurotrophic factor (GDNF) or the transcription factor c-Jun. The physicochemical properties of PEI-pDNA nanoparticles, morphology, size and charge, were shown to be suitable for gene delivery and demonstrated high Schwann cell transfection efficiency (60±13%) in vitro. While all three genes showed therapeutic potential in terms of enhancing neurotrophic cytokine production while promoting neurite outgrowth, delivery of the gene encoding for c-Jun showed the greatest capacity to enhance regenerative cellular processes in vitro. Ultimately, this gene-activated NGC construct was shown to be capable of transfecting both Schwann cells (S42 cells) and neuronal cells (PC12 and dorsal root ganglia) in vitro, demonstrating potential for future therapeutic applications in vivo. The basic requirements of biomaterial-based nerve guidance conduits have now been well established and include being able to bridge a nerve injury to support macroscopic guidance between nerve stumps, while being strong enough to withstand longitudinal tension and circumferential compression, in addition to being mechanically sound to facilitate surgical handling and implantation. While meeting these criteria, conduits are still limited to the treatment of small defects clinically and might benefit from additional biochemical stimuli to enhance repair for the effective treatment of larger injuries. In this study, a gene activated conduit was successfully developed by incorporating non-viral nanoparticles capable of efficient Schwann cell and neuronal cell transfection with therapeutic genes in vitro, which showed potential to enhance repair in future applications particularly when taking advantage of the transcription factor c-Jun. This innovative approach may provide an alternative to conduits used as platforms for the delivery neurotrophic factors or genetically modified cells (viral gene therapy), and a potential solution for the unmet clinical need to repair large peripheral nerve injury effectively. Copyright © 2018. Published by Elsevier Ltd.

Healthcare provider perceptions of the role of interprofessional care in access to and outcomes of primary care in an underserved area.

PubMed

Wan, Shaowei; Teichman, Peter G; Latif, David; Boyd, Jennifer; Gupta, Rahul

2018-03-01

To meet the needs of an aging population who often have multiple chronic conditions, interprofessional care is increasingly adopted by patient-centred medical homes and Accountable Care Organisations to improve patient care coordination and decrease costs in the United States, especially in underserved areas with primary care workforce shortages. In this cross-sectional survey across multiple clinical settings in an underserved area, healthcare providers perceived overall outcomes associated with interprofessional care teams as positive. This included healthcare providers' beliefs that interprofessional care teams improved patient outcomes, increased clinic efficiency, and enhanced care coordination and patient follow-up. Teams with primary care physician available each day were perceived as better able to coordinate care and follow up with patients (p = .031), while teams that included clinical pharmacists were perceived as preventing medication-associated problems (p < .0001). Healthcare providers perceived the interprofessional care model as a useful strategy to improve various outcomes across different clinical settings in the context of a shortage of primary care physicians.

The KALI multi-arm robot programming and control environment

NASA Technical Reports Server (NTRS)

Backes, Paul; Hayati, Samad; Hayward, Vincent; Tso, Kam

1989-01-01

The KALI distributed robot programming and control environment is described within the context of its use in the Jet Propulsion Laboratory (JPL) telerobot project. The purpose of KALI is to provide a flexible robot programming and control environment for coordinated multi-arm robots. Flexibility, both in hardware configuration and software, is desired so that it can be easily modified to test various concepts in robot programming and control, e.g., multi-arm control, force control, sensor integration, teleoperation, and shared control. In the programming environment, user programs written in the C programming language describe trajectories for multiple coordinated manipulators with the aid of KALI function libraries. A system of multiple coordinated manipulators is considered within the programming environment as one motion system. The user plans the trajectory of one controlled Cartesian frame associated with a motion system and describes the positions of the manipulators with respect to that frame. Smooth Cartesian trajectories are achieved through a blending of successive path segments. The manipulator and load dynamics are considered during trajectory generation so that given interface force limits are not exceeded.

Anharmonic Rovibrational Partition Functions for Fluxional Species at High Temperatures via Monte Carlo Phase Space Integrals

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jasper, Ahren W.; Gruey, Zackery B.; Harding, Lawrence B.

Monte Carlo phase space integration (MCPSI) is used to compute full dimensional and fully anharmonic, but classical, rovibrational partition functions for 22 small- and medium-sized molecules and radicals. Several of the species considered here feature multiple minima and low-frequency nonlocal motions, and efficiently sampling these systems is facilitated using curvilinear (stretch, bend, and torsion) coordinates. The curvilinear coordinate MCPSI method is demonstrated to be applicable to the treatment of fluxional species with complex rovibrational structures and as many as 21 fully coupled rovibrational degrees of freedom. Trends in the computed anharmonicity corrections are discussed. For many systems, rovibrational anharmonicities atmore » elevated temperatures are shown to vary consistently with the number of degrees of freedom and with temperature once rovibrational coupling and torsional anharmonicity are accounted for. Larger corrections are found for systems with complex vibrational structures, such as systems with multiple large-amplitude modes and/or multiple minima.« less

Adaptive Backstepping-Based Neural Tracking Control for MIMO Nonlinear Switched Systems Subject to Input Delays.

PubMed

Niu, Ben; Li, Lu

2018-06-01

This brief proposes a new neural-network (NN)-based adaptive output tracking control scheme for a class of disturbed multiple-input multiple-output uncertain nonlinear switched systems with input delays. By combining the universal approximation ability of radial basis function NNs and adaptive backstepping recursive design with an improved multiple Lyapunov function (MLF) scheme, a novel adaptive neural output tracking controller design method is presented for the switched system. The feature of the developed design is that different coordinate transformations are adopted to overcome the conservativeness caused by adopting a common coordinate transformation for all subsystems. It is shown that all the variables of the resulting closed-loop system are semiglobally uniformly ultimately bounded under a class of switching signals in the presence of MLF and that the system output can follow the desired reference signal. To demonstrate the practicability of the obtained result, an adaptive neural output tracking controller is designed for a mass-spring-damper system.

Women Facing the Multiple Role Challenge. Adult Women Studying Social Work and Adult Education in Canada: A Study of Their Multiple Role Experiences and of Supports Available to Them. Final Report.

ERIC Educational Resources Information Center

Home, Alice M.

A study examined the multiple role experiences of 20 adult women studying social work and adult education in 7 programs throughout Canada and the supports available to the women. Also interviewed during the study were two professors and the department head from each program, a field instructor, several program coordinators, and five employers.…

Mechanisms of stress in the brain.

PubMed

McEwen, Bruce S; Bowles, Nicole P; Gray, Jason D; Hill, Matthew N; Hunter, Richard G; Karatsoreos, Ilia N; Nasca, Carla

2015-10-01

The brain is the central organ involved in perceiving and adapting to social and physical stressors via multiple interacting mediators, from the cell surface to the cytoskeleton to epigenetic regulation and nongenomic mechanisms. A key result of stress is structural remodeling of neural architecture, which may be a sign of successful adaptation, whereas persistence of these changes when stress ends indicates failed resilience. Excitatory amino acids and glucocorticoids have key roles in these processes, along with a growing list of extra- and intracellular mediators that includes endocannabinoids and brain-derived neurotrophic factor (BDNF). The result is a continually changing pattern of gene expression mediated by epigenetic mechanisms involving histone modifications and CpG methylation and hydroxymethylation as well as by the activity of retrotransposons that may alter genomic stability. Elucidation of the underlying mechanisms of plasticity and vulnerability of the brain provides a basis for understanding the efficacy of interventions for anxiety and depressive disorders as well as age-related cognitive decline.

Suppression of Inflammatory Demyelinaton and Axon Degeneration through Inhibiting Kv3 Channels

PubMed Central

Jukkola, Peter; Gu, Yuanzheng; Lovett-Racke, Amy E.; Gu, Chen

2017-01-01

The development of neuroprotective and repair strategies for treating progressive multiple sclerosis (MS) requires new insights into axonal injury. 4-aminopyridine (4-AP), a blocker of voltage-gated K+ (Kv) channels, is used in symptomatic treatment of progressive MS, but the underlying mechanism remains unclear. Here we report that deleting Kv3.1—the channel with the highest 4-AP sensitivity—reduces clinical signs in experimental autoimmune encephalomyelitis (EAE), a mouse model for MS. In Kv3.1 knockout (KO) mice, EAE lesions in sensory and motor tracts of spinal cord were markedly reduced, and radial astroglia were activated with increased expression of brain derived neurotrophic factor (BDNF). Kv3.3/Kv3.1 and activated BDNF receptors were upregulated in demyelinating axons in EAE and MS lesions. In spinal cord myelin coculture, BDNF treatment promoted myelination, and neuronal firing via altering channel expression. Therefore, suppressing Kv3.1 alters neural circuit activity, which may enhance BNDF signaling and hence protect axons from inflammatory insults. PMID:29123469

Stem Cell Therapy: Repurposing Cell-Based Regenerative Medicine Beyond Cell Replacement.

PubMed

Napoli, Eleonora; Lippert, Trenton; Borlongan, Cesar V

2018-02-27

Stem cells exhibit simple and naive cellular features, yet their exact purpose for regenerative medicine continues to elude even the most elegantly designed research paradigms from developmental biology to clinical therapeutics. Based on their capacity to divide indefinitely and their dynamic differentiation into any type of tissue, the advent of transplantable stem cells has offered a potential treatment for aging-related and injury-mediated diseases. Recent laboratory evidence has demonstrated that transplanted human neural stem cells facilitate endogenous reparative mechanisms by initiating multiple regenerative processes in the brain neurogenic areas. Within these highly proliferative niches reside a myriad of potent regenerative molecules, including anti-inflammatory cytokines, proteomes, and neurotrophic factors, altogether representing a biochemical cocktail vital for restoring brain function in the aging and diseased brain. Here, we advance the concept of therapeutically repurposing stem cells not towards cell replacement per se, but rather exploiting the cells' intrinsic properties to serve as the host brain regenerative catalysts.

Microglia promote learning-dependent synapse formation through BDNF

PubMed Central

Parkhurst, Christopher N.; Yang, Guang; Ninan, Ipe; Savas, Jeffrey N.; Yates, John R.; Lafaille, Juan J.; Hempstead, Barbara L.; Littman, Dan R.; Gan, Wen-Biao

2014-01-01

SUMMARY Microglia are the resident macrophages of the central nervous system and their functions have been extensively studied in various brain pathologies. The physiological roles of microglia in brain plasticity and function, however, remain unclear. To address this question, we generated CX3CR1CreER mice expressing tamoxifen-inducible Cre recombinase that allow for specific manipulation of gene function in microglia. Using CX3CR1CreER to drive diphtheria toxin receptor expression in microglia, we found that microglia could be specifically depleted from the brain upon diphtheria toxin administration. Mice depleted of microglia show deficits in multiple learning tasks and a significant reduction in motor learning-dependent synapse formation. Furthermore, Cre-dependent removal of brain-derived neurotrophic factor (BDNF) from microglia largely recapitulated the effects of microglia depletion. Microglial BDNF increases neuronal TrkB phosphorylation, a key mediator of synaptic plasticity. Together, our findings reveal important physiological functions of microglia in learning and memory by promoting learning-related synapse formation through BDNF signaling. PMID:24360280

A comprehensive multiomics approach toward understanding the relationship between aging and dementia.

PubMed

Currais, Antonio; Goldberg, Joshua; Farrokhi, Catherine; Chang, Max; Prior, Marguerite; Dargusch, Richard; Daugherty, Daniel; Armando, Aaron; Quehenberger, Oswald; Maher, Pamela; Schubert, David

2015-11-01

Because age is the greatest risk factor for sporadic Alzheimer's disease (AD), phenotypic screens based upon old age-associated brain toxicities were used to develop the potent neurotrophic drug J147. Since certain aspects of aging may be primary cause of AD, we hypothesized that J147 would be effective against AD-associated pathology in rapidly aging SAMP8 mice and could be used to identify some of the molecular contributions of aging to AD. An inclusive and integrative multiomics approach was used to investigate protein and gene expression, metabolite levels, and cognition in old and young SAMP8 mice. J147 reduced cognitive deficits in old SAMP8 mice, while restoring multiple molecular markers associated with human AD, vascular pathology, impaired synaptic function, and inflammation to those approaching the young phenotype. The extensive assays used in this study identified a subset of molecular changes associated with aging that may be necessary for the development of AD.

Modulation of Mitochondrial Complex I Activity Averts Cognitive Decline in Multiple Animal Models of Familial Alzheimer's Disease

PubMed Central

Zhang, Liang; Zhang, Song; Maezawa, Izumi; Trushin, Sergey; Minhas, Paras; Pinto, Matthew; Jin, Lee-Way; Prasain, Keshar; Nguyen, Thi D.T.; Yamazaki, Yu; Kanekiyo, Takahisa; Bu, Guojun; Gateno, Benjamin; Chang, Kyeong-Ok; Nath, Karl A.; Nemutlu, Emirhan; Dzeja, Petras; Pang, Yuan-Ping; Hua, Duy H.; Trushina, Eugenia

2015-01-01

Development of therapeutic strategies to prevent Alzheimer's disease (AD) is of great importance. We show that mild inhibition of mitochondrial complex I with small molecule CP2 reduces levels of amyloid beta and phospho-Tau and averts cognitive decline in three animal models of familial AD. Low-mass molecular dynamics simulations and biochemical studies confirmed that CP2 competes with flavin mononucleotide for binding to the redox center of complex I leading to elevated AMP/ATP ratio and activation of AMP-activated protein kinase in neurons and mouse brain without inducing oxidative damage or inflammation. Furthermore, modulation of complex I activity augmented mitochondrial bioenergetics increasing coupling efficiency of respiratory chain and neuronal resistance to stress. Concomitant reduction of glycogen synthase kinase 3β activity and restoration of axonal trafficking resulted in elevated levels of neurotrophic factors and synaptic proteins in adult AD mice. Our results suggest that metabolic reprogramming induced by modulation of mitochondrial complex I activity represents promising therapeutic strategy for AD. PMID:26086035

Chemical Modification of the Multi-Target Neuroprotective Compound Fisetin

PubMed Central

Chiruta, Chandramouli; Schubert, David; Dargusch, Richard; Maher, Pamela

2012-01-01

Many factors are implicated in age-related CNS disorders making it unlikely that modulating only a single factor will provide effective treatment. Perhaps a better approach is to identify small molecules that have multiple biological activities relevant to the maintenance of brain function. Recently, we identified an orally active, neuroprotective and cognition-enhancing molecule, the flavonoid fisetin, that is effective in several animal models of CNS disorders. Fisetin has direct antioxidant activity and can also increase the intracellular levels of glutathione (GSH), the major endogenous antioxidant. In addition, fisetin has both neurotrophic and anti-inflammatory activity. However, its relatively high EC50 in cell based assays, low lipophilicity, high tPSA and poor bioavailability suggest that there is room for medicinal chemical improvement. Here we describe a multi-tiered approach to screening that has allowed us to identify fisetin derivatives with significantly enhanced activity in an in vitro neuroprotection model while at the same time maintaining other key activities. PMID:22192055

ProBDNF and mature BDNF as punishment and reward signals for synapse elimination at mouse neuromuscular junctions.

PubMed

Je, H Shawn; Yang, Feng; Ji, Yuanyuan; Potluri, Srilatha; Fu, Xiu-Qing; Luo, Zhen-Ge; Nagappan, Guhan; Chan, Jia Pei; Hempstead, Barbara; Son, Young-Jin; Lu, Bai

2013-06-12

During development, mammalian neuromuscular junctions (NMJs) transit from multiple-innervation to single-innervation through axonal competition via unknown molecular mechanisms. Previously, using an in vitro model system, we demonstrated that the postsynaptic secretion of pro-brain-derived neurotrophic factor (proBDNF) stabilizes or eliminates presynaptic axon terminals, depending on its proteolytic conversion at synapses. Here, using developing mouse NMJs, we obtained in vivo evidence that proBDNF and mature BDNF (mBDNF) play roles in synapse elimination. We observed that exogenous proBDNF promoted synapse elimination, whereas mBDNF infusion substantially delayed synapse elimination. In addition, pharmacological inhibition of the proteolytic conversion of proBDNF to mBDNF accelerated synapse elimination via activation of p75 neurotrophin receptor (p75(NTR)). Furthermore, the inhibition of both p75(NTR) and sortilin signaling attenuated synapse elimination. We propose a model in which proBDNF and mBDNF serve as potential "punishment" and "reward" signals for inactive and active terminals, respectively, in vivo.

Effects of brain-derived neurotrophic factor (BDNF) on the cochlear nucleus in cats deafened as neonates.

PubMed

Kandathil, Cherian K; Stakhovskaya, Olga; Leake, Patricia A

2016-12-01

Many previous studies have shown significant neurotrophic effects of intracochlear delivery of BDNF in preventing degeneration of cochlear spiral ganglion (SG) neurons after deafness in rodents and our laboratory has shown similar results in developing cats deafened prior to hearing onset. This study examined the morphology of the cochlear nucleus (CN) in a group of neonatally deafened cats from a previous study in which infusion of BDNF elicited a significant improvement in survival of the SG neurons. Five cats were deafened by systemic injections of neomycin sulfate (60 mg/kg, SQ, SID) starting one day after birth, and continuing for 16-18 days until auditory brainstem response (ABR) testing demonstrated profound bilateral hearing loss. The animals were implanted unilaterally at about 1 month of age using custom-designed electrodes with a drug-delivery cannula connected to an osmotic pump. BDNF (94 μg/ml; 0.25 μl/hr) was delivered for 10 weeks. The animals were euthanized and studied at 14-23 weeks of age. Consistent with the neurotrophic effects of BDNF on SG survival, the total CN volume in these animals was significantly larger on the BDNF-treated side than on the contralateral side. However, total CN volume, both ipsi- and contralateral to the implants in these deafened juvenile animals, was markedly smaller than the CN in normal adult animals, reflecting the severe effects of deafness on the central auditory system during development. Data from the individual major CN subdivisions (DCN, Dorsal Cochlear Nucleus; PVCN, Posteroventral Cochlear Nucleus; AVCN, Anteroventral Cochlear Nucleus) also were analyzed. A significant difference was observed between the BDNF-treated and control sides only in the AVCN. Measurements of the cross-sectional areas of spherical cells showed that cells were significantly larger in the AVCN ipsilateral to the implant than on the contralateral side. Further, the numerical density of spherical cells was significantly lower in the AVCN ipsilateral to the implant than on the contralateral side, consistent with the larger AVCN volume observed with BDNF treatment. Together, findings indicate significant neurotrophic effects of intracochlear BDNF infusion on the developing CN. Copyright © 2016 Elsevier B.V. All rights reserved.

White Matter Tract Integrity in Alzheimer's Disease vs. Late Onset Bipolar Disorder and Its Correlation with Systemic Inflammation and Oxidative Stress Biomarkers.

PubMed

Besga, Ariadna; Chyzhyk, Darya; Gonzalez-Ortega, Itxaso; Echeveste, Jon; Graña-Lecuona, Marina; Graña, Manuel; Gonzalez-Pinto, Ana

2017-01-01

Background: Late Onset Bipolar Disorder (LOBD) is the development of Bipolar Disorder (BD) at an age above 50 years old. It is often difficult to differentiate from other aging dementias, such as Alzheimer's Disease (AD), because they share cognitive and behavioral impairment symptoms. Objectives: We look for WM tract voxel clusters showing significant differences when comparing of AD vs. LOBD, and its correlations with systemic blood plasma biomarkers (inflammatory, neurotrophic factors, and oxidative stress). Materials: A sample of healthy controls (HC) ( n = 19), AD patients ( n = 35), and LOBD patients ( n = 24) was recruited at the Alava University Hospital. Blood plasma samples were obtained at recruitment time and analyzed to extract the inflammatory, oxidative stress, and neurotrophic factors. Several modalities of MRI were acquired for each subject, Methods: Fractional anisotropy (FA) coefficients are obtained from diffusion weighted imaging (DWI). Tract based spatial statistics (TBSS) finds FA skeleton clusters of WM tract voxels showing significant differences for all possible contrasts between HC, AD, and LOBD. An ANOVA F -test over all contrasts is carried out. Results of F -test are used to mask TBSS detected clusters for the AD > LOBD and LOBD > AD contrast to select the image clusters used for correlation analysis. Finally, Pearson's correlation coefficients between FA values at cluster sites and systemic blood plasma biomarker values are computed. Results: The TBSS contrasts with by ANOVA F -test has identified strongly significant clusters in the forceps minor, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, and cingulum gyrus. The correlation analysis of these tract clusters found strong negative correlation of AD with the nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) blood biomarkers. Negative correlation of AD and positive correlation of LOBD with inflammation biomarker IL6 was also found. Conclusion: TBSS voxel clusters tract atlas localizations are consistent with greater behavioral impairment and mood disorders in LOBD than in AD. Correlation analysis confirms that neurotrophic factors (i.e., NGF, BDNF) play a great role in AD while are absent in LOBD pathophysiology. Also, correlation results of IL1 and IL6 suggest stronger inflammatory effects in LOBD than in AD.

A peptide fragment of ependymin neurotrophic factor uses protein kinase C and the mitogen-activated protein kinase pathway to activate c-Jun N-terminal kinase and a functional AP-1 containing c-Jun and c-Fos proteins in mouse NB2a cells.

PubMed

Adams, David S; Hasson, Brendan; Boyer-Boiteau, Anne; El-Khishin, Adam; Shashoua, Victor E

2003-05-01

Ependymin (EPN) is a goldfish brain neurotrophic factor previously shown to function in a variety of cellular events related to long-term memory formation and neuronal regeneration. CMX-8933, an 8-amino-acid synthetic peptide fragment of EPN, was designed for aiding an investigation of the biological properties of this glycoprotein. We reported from previous studies that treatment of mouse neuroblastoma (NB2a) cultures with CMX-8933 promotes activation of transcription factor AP-1, a characteristic previously associated with the following full-length neurotrophic factors: nerve growth factor, neurotropin-3, and brain-derived neurotrophic factor. The CMX-8933-activated AP-1 specifically bound an AP-1 consensus probe and appeared to contain c-Jun and c-Fos protein components in antibody supershift experiments. Because AP-1 influences a variety of positive and negative cellular processes, determined in part by its exact protein composition and mechanism of activation, we extended these initial AP-1 observations in the current study to confirm the identity of the CMX-8933-activated c-Jun and c-Fos components. CMX-8933 increases the enzymatic activity of c-Jun N-terminal kinase (JNK), increases the phosphorylation of JNK and c-Jun proteins, and increases the cellular titers of c-Jun and c-Fos mRNAs. Furthermore, the AP-1 activated by CMX-8933 is functional, insofar as it transactivates both synthetic and natural AP-1-dependent reporter plasmids. Inhibition studies indicate that activation of the 8933-induced AP-1 occurs via the mitogen-activated protein kinase pathway. These data are in agreement with the recently proposed model for the conversion of short- to long-term synaptic plasticity and memory, in which a JNK-activated transcription factor AP-1, containing c-Jun and c-Fos components, functions at the top of a hierarchy of transcription factors known to regulate long-term neural plasticity. Copyright 2003 Wiley-Liss, Inc.

The coordinating evaluation and spatial correlation analysis of CSGC: A case study of Henan province, China.

PubMed

Xie, Mingxia; Wang, Jiayao; Chen, Ke

2017-01-01

This study investigates the basic characteristics and proposes a concept for the complex system of geographical conditions (CSGC). By analyzing the DPSIR model and its correlation with the index system, we selected indexes for geographical conditions according to the resources, ecology, environment, economy and society parameters to build a system. This system consists of four hierarchies: index, classification, element and target levels. We evaluated the elements or indexes of the complex system using the TOPSIS method and a general model coordinating multiple complex systems. On this basis, the coordination analysis experiment of geographical conditions is applied to cities in the Henan province in China. The following conclusions were reached: ①According to the pressure, state and impact of geographical conditions, relatively consistent measures are taken around the city, but with conflicting results. ②The coordination degree of geographical conditions is small among regions showing large differences in classification index value. The degree of coordination of such regions is prone to extreme values; however, the smaller the difference the larger the coordination degree. ③The coordinated development of geographical conditions in the Henan province is at the stage of the point axis.