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Sample records for brain reveals unexpected

  1. Unexpected events induce motor slowing via a brain mechanism for action-stopping with global suppressive effects.

    PubMed

    Wessel, Jan R; Aron, Adam R

    2013-11-20

    When an unexpected event occurs in everyday life (e.g., a car honking), one experiences a slowing down of ongoing action (e.g., of walking into the street). Motor slowing following unexpected events is a ubiquitous phenomenon, both in laboratory experiments as well as such everyday situations, yet the underlying mechanism is unknown. We hypothesized that unexpected events recruit the same inhibition network in the brain as does complete cancellation of an action (i.e., action-stopping). Using electroencephalography and independent component analysis in humans, we show that a brain signature of successful outright action-stopping also exhibits activity following unexpected events, and more so in blocks with greater motor slowing. Further, using transcranial magnetic stimulation to measure corticospinal excitability, we show that an unexpected event has a global motor suppressive effect, just like outright action-stopping. Thus, unexpected events recruit a common mechanism with outright action-stopping, moreover with global suppressive effects. These findings imply that we can now leverage the considerable extant knowledge of the neural architecture and functional properties of the stopping system to better understand the processing of unexpected events, including perhaps how they induce distraction via global suppression.

  2. Unexpected Events Induce Motor Slowing via a Brain Mechanism for Action-Stopping with Global Suppressive Effects

    PubMed Central

    Aron, Adam R.

    2013-01-01

    When an unexpected event occurs in everyday life (e.g., a car honking), one experiences a slowing down of ongoing action (e.g., of walking into the street). Motor slowing following unexpected events is a ubiquitous phenomenon, both in laboratory experiments as well as such everyday situations, yet the underlying mechanism is unknown. We hypothesized that unexpected events recruit the same inhibition network in the brain as does complete cancellation of an action (i.e., action-stopping). Using electroencephalography and independent component analysis in humans, we show that a brain signature of successful outright action-stopping also exhibits activity following unexpected events, and more so in blocks with greater motor slowing. Further, using transcranial magnetic stimulation to measure corticospinal excitability, we show that an unexpected event has a global motor suppressive effect, just like outright action-stopping. Thus, unexpected events recruit a common mechanism with outright action-stopping, moreover with global suppressive effects. These findings imply that we can now leverage the considerable extant knowledge of the neural architecture and functional properties of the stopping system to better understand the processing of unexpected events, including perhaps how they induce distraction via global suppression. PMID:24259571

  3. The Crystal Structures of EAP Domains from Staphylococcus aureus Reveal an Unexpected Homology to Bacterial Superantigens

    SciTech Connect

    Geisbrecht, B V; Hamaoka, B Y; Perman, B; Zemla, A; Leahy, D J

    2005-10-14

    The Eap (extracellular adherence protein) of Staphylococcus aureus functions as a secreted virulence factor by mediating interactions between the bacterial cell surface and several extracellular host proteins. Eap proteins from different Staphylococcal strains consist of four to six tandem repeats of a structurally uncharacterized domain (EAP domain). We have determined the three-dimensional structures of three different EAP domains to 1.8, 2.2, and 1.35 {angstrom} resolution, respectively. These structures reveal a core fold that is comprised of an {alpha}-helix lying diagonally across a five-stranded, mixed {beta}-sheet. Comparison of EAP domains with known structures reveals an unexpected homology with the C-terminal domain of bacterial superantigens. Examination of the structure of the superantigen SEC2 bound to the {beta}-chain of a T-cell receptor suggests a possible ligand-binding site within the EAP domain (Fields, B. A., Malchiodi, E. L., Li, H., Ysern, X., Stauffacher, C. V., Schlievert, P. M., Karjalainen, K., and Mariuzza, R. (1996) Nature 384, 188-192). These results provide the first structural characterization of EAP domains, relate EAP domains to a large class of bacterial toxins, and will guide the design of future experiments to analyze EAP domain structure/function relationships.

  4. Kinase inhibitor profiling reveals unexpected opportunities to inhibit disease-associated mutant kinases

    PubMed Central

    Duong-Ly, Krisna C.; Devarajan, Karthik; Liang, Shuguang; Horiuchi, Kurumi Y.; Wang, Yuren; Ma, Haiching; Peterson, Jeffrey R.

    2016-01-01

    Summary Small-molecule kinase inhibitors have typically been designed to inhibit wild-type kinases rather than the mutant forms that frequently arise in diseases such as cancer. Mutations can have serious clinical implications by increasing kinase catalytic activity or conferring therapeutic resistance. To identify opportunities to repurpose inhibitors against disease-associated mutant kinases, we conducted a large-scale functional screen of 183 known kinase inhibitors against 76 recombinant, mutant kinases. The results revealed lead compounds with activity against clinically important mutant kinases including ALK, LRRK2, RET, and EGFR as well as unexpected opportunities for repurposing FDA-approved kinase inhibitors as leads for additional indications. Furthermore, using T674I PDGFRα as an example, we show how single-dose screening data can provide predictive structure-activity data to guide subsequent inhibitor optimization. This study provides a resource for the development of inhibitors against numerous disease-associated mutant kinases and illustrates the potential of unbiased profiling as an approach to compound-centric inhibitor development. PMID:26776524

  5. Metatranscriptome Analysis of Aquifer Samples Reveals Unexpected Metabolic Lifestyles Relevant to Active Biogeochemical Cycling

    NASA Astrophysics Data System (ADS)

    Beller, H. R.; Jewell, T. N. M.; Karaoz, U.; Banfield, J. F.; Brodie, E.; Williams, K. H.

    2015-12-01

    Modern molecular ecology techniques are revealing the metabolic potential of uncultivated microorganisms, but there is still much to be learned about the actual biogeochemical roles of microbes that have cultivated relatives. Here, we present metatranscriptomic and metagenomic data from a field study that provides evidence of coupled redox processes that have not been documented in cultivated relatives and, indeed, represent strains with metabolic traits that are novel with respect to closely related isolates. The data come from omics analysis of groundwater samples collected during an experiment in which nitrate (a native electron acceptor) was injected into a perennially suboxic aquifer in Rifle (CO). Transcriptional data indicated that just two groups of chemolithoautotrophic bacteria accounted for a very large portion (~80%) of overall community gene expression: (1) members of the Fe(II)-oxidizing Gallionellaceae family and (2) strains of the S-oxidizing species, Sulfurimonas denitrificans. Metabolic lifestyles for Gallionellaceae strains that were novel compared to cultivated representatives included nitrate-dependent Fe(II) oxidation and S oxidation. Evidence for these metabolisms included highly correlated temporal expression in binned data of nitrate reductase (e.g., narGHI) genes (which have never been reported in Gallionellaceae genomes) and Fe(II) oxidation genes (e.g., mtoA) or S oxidation genes (e.g., dsrE, aprA). Of the two most active strains of S. denitrificans, only one showed strong expression of S oxidation genes, whereas the other was apparently using an unexpected (as-yet unidentified) primary electron donor. Transcriptional data added considerable interpretive value to this study, as (1) metagenomic data would not have highlighted these organisms, which had a disproportionately large role in community metabolism relative to their populations, and (2) co-expression of coupled pathway genes could not be predicted based solely on metagenomic data.

  6. Unexpected detection of brain metastases by 18F-NaF PET/CT in a patient with lung cancer.

    PubMed

    Wu, Jiang; Zhu, Hong; Ji, Hengshan

    2013-11-01

    In recent years, the inconsistent supply of (99m)Tc and the increasingly widespread use of PET/CT have led to a renewed interest in PET/CT bone scans using (18)F-NaF. Recently, a 64-year-old man with biopsy-proven lung cancer underwent an (18)F-NaF PET/CT bone scan due to a shortage of (99m)Tc. Unexpectedly, multiple nodular foci of increased tracer uptake were present in the brain, whereas there were no definitive bone metastases detected. Subsequently, brain MRI confirmed the presence of brain metastases.

  7. Unexpected Recovery of Function after Severe Traumatic Brain Injury: The Limits of Early Neuroimaging-Based Outcome Prediction

    PubMed Central

    Edlow, Brian L.; Giacino, Joseph T.; Hirschberg, Ronald E.; Gerrard, Jason; Wu, Ona; Hochberg, Leigh R.

    2014-01-01

    Background Prognostication in the early stage of traumatic coma is a common challenge in the neuro-intensive care unit. We report the unexpected recovery of functional milestones (i.e., consciousness, communication, and community reintegration) in a 19-year-old man who sustained a severe traumatic brain injury. The early magnetic resonance imaging (MRI) findings, at the time, suggested a poor prognosis. Methods During the first year of the patient’s recovery, MRI with diffusion tensor imaging (DTI) and T2*-weighted imaging was performed on day 8 (coma), day 44 (minimally conscious state), day 198 (post-traumatic confusional state), and day 366 (community reintegration). Mean apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values in the corpus callosum, cerebral hemispheric white matter and thalamus were compared with clinical assessments using the Disability Rating Scale (DRS). Results Extensive diffusion restriction in the corpus callosum and bihemispheric white matter was observed on day 8, with ADC values in a range typically associated with neurotoxic injury (230 to 400 × 10−6 mm2/sec). T2*-weighted MRI revealed widespread hemorrhagic axonal injury in the cerebral hemispheres, corpus callosum, and brainstem. Despite the presence of severe axonal injury on early MRI, the patient regained the ability to communicate and perform activities of daily living independently at one year post-injury (DRS = 8). Conclusions MRI data should be interpreted with caution when prognosticating for patients in traumatic coma. Recovery of consciousness and community reintegration are possible even when extensive traumatic axonal injury is demonstrated by early MRI. PMID:23860665

  8. Unexpected divergence and lack of divergence revealed in continental Asian Cyornis flycatchers (Aves: Muscicapidae).

    PubMed

    Zhang, Zhen; Wang, Xiaoyang; Huang, Yuan; Olsson, Urban; Martinez, Jonathan; Alström, Per; Lei, Fumin

    2016-01-01

    The flycatcher genus Cyornis (Aves: Muscicapidae) comprises 25 species with Oriental distributions. Their relationships are poorly known. We analyzed the phylogenetic relationships of 70 individuals from 12 species and several subspecies of Cyornis based on three mitochondrial genes and five nuclear introns, with special focus on Chinese and Vietnamese populations of the monotypic C. hainanus and polytypic C. rubeculoides. We found no support for inclusion of C. concretus in Cyornis. Deep divergences were observed among different subspecies of C. banyumas and C. rubeculoides. C. rubeculoides glaucicomans was also shown to have a highly distinctive song, and we propose that it is treated as a distinctive Chinese endemic species, C. glaucicomans. In contrast, the south Vietnamese C. rubeculoides klossi, which has a disjunct distribution from the other subspecies of C. rubeculoides, along with a recently discovered population in Guangdong Province (China) with several plumage features reminiscent of C. r. klossi, were indistinguishable in all loci analyzed from the phenotypically markedly different C. hainanus. More research is needed to elucidate the reasons for this unexpected pattern.

  9. Citizen Science Reveals Unexpected Continental-Scale Evolutionary Change in a Model Organism

    PubMed Central

    Silvertown, Jonathan; Cook, Laurence; Cameron, Robert; Dodd, Mike; McConway, Kevin; Worthington, Jenny; Skelton, Peter; Anton, Christian; Bossdorf, Oliver; Baur, Bruno; Schilthuizen, Menno; Fontaine, Benoît; Sattmann, Helmut; Bertorelle, Giorgio; Correia, Maria; Oliveira, Cristina; Pokryszko, Beata; Ożgo, Małgorzata; Stalažs, Arturs; Gill, Eoin; Rammul, Üllar; Sólymos, Péter; Féher, Zoltan; Juan, Xavier

    2011-01-01

    Organisms provide some of the most sensitive indicators of climate change and evolutionary responses are becoming apparent in species with short generation times. Large datasets on genetic polymorphism that can provide an historical benchmark against which to test for recent evolutionary responses are very rare, but an exception is found in the brown-lipped banded snail (Cepaea nemoralis). This species is sensitive to its thermal environment and exhibits several polymorphisms of shell colour and banding pattern affecting shell albedo in the majority of populations within its native range in Europe. We tested for evolutionary changes in shell albedo that might have been driven by the warming of the climate in Europe over the last half century by compiling an historical dataset for 6,515 native populations of C. nemoralis and comparing this with new data on nearly 3,000 populations. The new data were sampled mainly in 2009 through the Evolution MegaLab, a citizen science project that engaged thousands of volunteers in 15 countries throughout Europe in the biggest such exercise ever undertaken. A known geographic cline in the frequency of the colour phenotype with the highest albedo (yellow) was shown to have persisted and a difference in colour frequency between woodland and more open habitats was confirmed, but there was no general increase in the frequency of yellow shells. This may have been because snails adapted to a warming climate through behavioural thermoregulation. By contrast, we detected an unexpected decrease in the frequency of Unbanded shells and an increase in the Mid-banded morph. Neither of these evolutionary changes appears to be a direct response to climate change, indicating that the influence of other selective agents, possibly related to changing predation pressure and habitat change with effects on micro-climate. PMID:21556137

  10. Citizen science reveals unexpected continental-scale evolutionary change in a model organism.

    PubMed

    Silvertown, Jonathan; Cook, Laurence; Cameron, Robert; Dodd, Mike; McConway, Kevin; Worthington, Jenny; Skelton, Peter; Anton, Christian; Bossdorf, Oliver; Baur, Bruno; Schilthuizen, Menno; Fontaine, Benoît; Sattmann, Helmut; Bertorelle, Giorgio; Correia, Maria; Oliveira, Cristina; Pokryszko, Beata; Ożgo, Małgorzata; Stalažs, Arturs; Gill, Eoin; Rammul, Üllar; Sólymos, Péter; Féher, Zoltan; Juan, Xavier

    2011-04-27

    Organisms provide some of the most sensitive indicators of climate change and evolutionary responses are becoming apparent in species with short generation times. Large datasets on genetic polymorphism that can provide an historical benchmark against which to test for recent evolutionary responses are very rare, but an exception is found in the brown-lipped banded snail (Cepaea nemoralis). This species is sensitive to its thermal environment and exhibits several polymorphisms of shell colour and banding pattern affecting shell albedo in the majority of populations within its native range in Europe. We tested for evolutionary changes in shell albedo that might have been driven by the warming of the climate in Europe over the last half century by compiling an historical dataset for 6,515 native populations of C. nemoralis and comparing this with new data on nearly 3,000 populations. The new data were sampled mainly in 2009 through the Evolution MegaLab, a citizen science project that engaged thousands of volunteers in 15 countries throughout Europe in the biggest such exercise ever undertaken. A known geographic cline in the frequency of the colour phenotype with the highest albedo (yellow) was shown to have persisted and a difference in colour frequency between woodland and more open habitats was confirmed, but there was no general increase in the frequency of yellow shells. This may have been because snails adapted to a warming climate through behavioural thermoregulation. By contrast, we detected an unexpected decrease in the frequency of Unbanded shells and an increase in the Mid-banded morph. Neither of these evolutionary changes appears to be a direct response to climate change, indicating that the influence of other selective agents, possibly related to changing predation pressure and habitat change with effects on micro-climate.

  11. An Unexpected Transient Breakdown of the Blood Brain Barrier Triggers Passage of Large Intravenously Administered Nanoparticles

    NASA Astrophysics Data System (ADS)

    Smith, Nicole M.; Gachulincova, Ivana; Ho, Diwei; Bailey, Charlotte; Bartlett, Carole A.; Norret, Marck; Murphy, John; Buckley, Alysia; Rigby, Paul J.; House, Michael J.; St. Pierre, Timothy; Fitzgerald, Melinda; Iyer, K. Swaminathan; Dunlop, Sarah A.

    2016-03-01

    The highly restrictive blood-brain barrier (BBB) plays a critically important role in maintaining brain homeostasis and is pivotal for proper neuronal function. The BBB is currently considered the main limiting factor restricting the passage of large (up to 200 nm) intravenously administered nanoparticles to the brain. Breakdown of the barrier occurs as a consequence of cerebrovascular diseases and traumatic brain injury. In this article, we report that remote injuries in the CNS are also associated with BBB dysfunction. In particular, we show that a focal partial transection of the optic nerve triggers a previously unknown transient opening of the mammalian BBB that occurs in the visual centres. Importantly, we demonstrate that this transient BBB breakdown results in a dramatic change in the biodistribution of intravenously administered large polymeric nanoparticles which were previously deemed as BBB-impermeable.

  12. An Unexpected Transient Breakdown of the Blood Brain Barrier Triggers Passage of Large Intravenously Administered Nanoparticles

    PubMed Central

    Smith, Nicole M.; Gachulincova, Ivana; Ho, Diwei; Bailey, Charlotte; Bartlett, Carole A.; Norret, Marck; Murphy, John; Buckley, Alysia; Rigby, Paul J.; House, Michael J.; St. Pierre, Timothy; Fitzgerald, Melinda; Iyer, K. Swaminathan; Dunlop, Sarah A.

    2016-01-01

    The highly restrictive blood-brain barrier (BBB) plays a critically important role in maintaining brain homeostasis and is pivotal for proper neuronal function. The BBB is currently considered the main limiting factor restricting the passage of large (up to 200 nm) intravenously administered nanoparticles to the brain. Breakdown of the barrier occurs as a consequence of cerebrovascular diseases and traumatic brain injury. In this article, we report that remote injuries in the CNS are also associated with BBB dysfunction. In particular, we show that a focal partial transection of the optic nerve triggers a previously unknown transient opening of the mammalian BBB that occurs in the visual centres. Importantly, we demonstrate that this transient BBB breakdown results in a dramatic change in the biodistribution of intravenously administered large polymeric nanoparticles which were previously deemed as BBB-impermeable. PMID:26940762

  13. Unexpected Regularity in Swimming Behavior of Clausocalanus furcatus Revealed by a Telecentric 3D Computer Vision System

    PubMed Central

    Bianco, Giuseppe; Botte, Vincenzo; Dubroca, Laurent; Ribera d’Alcalà, Maurizio; Mazzocchi, Maria Grazia

    2013-01-01

    Planktonic copepods display a large repertoire of motion behaviors in a three-dimensional environment. Two-dimensional video observations demonstrated that the small copepod Clausocalanus furcatus, one the most widely distributed calanoids at low to medium latitudes, presented a unique swimming behavior that was continuous and fast and followed notably convoluted trajectories. Furthermore, previous observations indicated that the motion of C. furcatus resembled a random process. We characterized the swimming behavior of this species in three-dimensional space using a video system equipped with telecentric lenses, which allow tracking of zooplankton without the distortion errors inherent in common lenses. Our observations revealed unexpected regularities in the behavior of C. furcatus that appear primarily in the horizontal plane and could not have been identified in previous observations based on lateral views. Our results indicate that the swimming behavior of C. furcatus is based on a limited repertoire of basic kinematic modules but exhibits greater plasticity than previously thought. PMID:23826331

  14. Deep phenotyping of 89 xeroderma pigmentosum patients reveals unexpected heterogeneity dependent on the precise molecular defect.

    PubMed

    Fassihi, Hiva; Sethi, Mieran; Fawcett, Heather; Wing, Jonathan; Chandler, Natalie; Mohammed, Shehla; Craythorne, Emma; Morley, Ana M S; Lim, Rongxuan; Turner, Sally; Henshaw, Tanya; Garrood, Isabel; Giunti, Paola; Hedderly, Tammy; Abiona, Adesoji; Naik, Harsha; Harrop, Gemma; McGibbon, David; Jaspers, Nicolaas G J; Botta, Elena; Nardo, Tiziana; Stefanini, Miria; Young, Antony R; Sarkany, Robert P E; Lehmann, Alan R

    2016-03-01

    Xeroderma pigmentosum (XP) is a rare DNA repair disorder characterized by increased susceptibility to UV radiation (UVR)-induced skin pigmentation, skin cancers, ocular surface disease, and, in some patients, sunburn and neurological degeneration. Genetically, it is assigned to eight complementation groups (XP-A to -G and variant). For the last 5 y, the UK national multidisciplinary XP service has provided follow-up for 89 XP patients, representing most of the XP patients in the United Kingdom. Causative mutations, DNA repair levels, and more than 60 clinical variables relating to dermatology, ophthalmology, and neurology have been measured, using scoring systems to categorize disease severity. This deep phenotyping has revealed unanticipated heterogeneity of clinical features, between and within complementation groups. Skin cancer is most common in XP-C, XP-E, and XP-V patients, previously considered to be the milder groups based on cellular analyses. These patients have normal sunburn reactions and are therefore diagnosed later and are less likely to adhere to UVR protection. XP-C patients are specifically hypersensitive to ocular damage, and XP-F and XP-G patients appear to be much less susceptible to skin cancer than other XP groups. Within XP groups, different mutations confer susceptibility or resistance to neurological damage. Our findings on this large cohort of XP patients under long-term follow-up reveal that XP is more heterogeneous than has previously been appreciated. Our data now enable provision of personalized prognostic information and management advice for each XP patient, as well as providing new insights into the functions of the XP proteins. PMID:26884178

  15. Comparative analyses of developmental transcription factor repertoires in sponges reveal unexpected complexity of the earliest animals.

    PubMed

    Fortunato, Sofia A V; Adamski, Marcin; Adamska, Maja

    2015-12-01

    Developmental transcription factors (DTFs) control development of animals by affecting expression of target genes, some of which are transcription factors themselves. In bilaterians and cnidarians, conserved DTFs are involved in homologous processes such as gastrulation or specification of neurons. The genome of Amphimedon queenslandica, the first sponge to be sequenced, revealed that only a fraction of these conserved DTF families are present in demosponges. This finding was in line with the view that morphological complexity in the animal lineage correlates with developmental toolkit complexity. However, as the phylum Porifera is very diverse, Amphimedon's genome may not be representative of all sponges. The recently sequenced genomes of calcareous sponges Sycon ciliatum and Leucosolenia complicata allowed investigations of DTFs in a sponge lineage evolutionarily distant from demosponges. Surprisingly, the phylogenetic analyses of identified DTFs revealed striking differences between the calcareous sponges and Amphimedon. As these differences appear to be a result of independent gene loss events in the two sponge lineages, the last common ancestor of sponges had to possess a much more diverse repertoire of DTFs than extant sponges. Developmental expression of sponge homologs of genes involved in specification of the Bilaterian endomesoderm and the neurosensory cells suggests that roles of many DTFs date back to the last common ancestor of all animals. Strikingly, even DTFs displaying apparent pan-metazoan conservation of sequence and function are not immune to being lost from individual species genomes. The quest for a comprehensive picture of the developmental toolkit in the last common metazoan ancestor is thus greatly benefitting from the increasing accessibility of sequencing, allowing comparisons of multiple genomes within each phylum.

  16. Deep phenotyping of 89 xeroderma pigmentosum patients reveals unexpected heterogeneity dependent on the precise molecular defect

    PubMed Central

    Fassihi, Hiva; Sethi, Mieran; Fawcett, Heather; Wing, Jonathan; Chandler, Natalie; Mohammed, Shehla; Craythorne, Emma; Morley, Ana M. S.; Lim, Rongxuan; Turner, Sally; Henshaw, Tanya; Garrood, Isabel; Giunti, Paola; Hedderly, Tammy; Abiona, Adesoji; Naik, Harsha; Harrop, Gemma; McGibbon, David; Jaspers, Nicolaas G. J.; Botta, Elena; Nardo, Tiziana; Stefanini, Miria; Young, Antony R.; Sarkany, Robert P. E.; Lehmann, Alan R.

    2016-01-01

    Xeroderma pigmentosum (XP) is a rare DNA repair disorder characterized by increased susceptibility to UV radiation (UVR)-induced skin pigmentation, skin cancers, ocular surface disease, and, in some patients, sunburn and neurological degeneration. Genetically, it is assigned to eight complementation groups (XP-A to -G and variant). For the last 5 y, the UK national multidisciplinary XP service has provided follow-up for 89 XP patients, representing most of the XP patients in the United Kingdom. Causative mutations, DNA repair levels, and more than 60 clinical variables relating to dermatology, ophthalmology, and neurology have been measured, using scoring systems to categorize disease severity. This deep phenotyping has revealed unanticipated heterogeneity of clinical features, between and within complementation groups. Skin cancer is most common in XP-C, XP-E, and XP-V patients, previously considered to be the milder groups based on cellular analyses. These patients have normal sunburn reactions and are therefore diagnosed later and are less likely to adhere to UVR protection. XP-C patients are specifically hypersensitive to ocular damage, and XP-F and XP-G patients appear to be much less susceptible to skin cancer than other XP groups. Within XP groups, different mutations confer susceptibility or resistance to neurological damage. Our findings on this large cohort of XP patients under long-term follow-up reveal that XP is more heterogeneous than has previously been appreciated. Our data now enable provision of personalized prognostic information and management advice for each XP patient, as well as providing new insights into the functions of the XP proteins. PMID:26884178

  17. Deep phenotyping of 89 xeroderma pigmentosum patients reveals unexpected heterogeneity dependent on the precise molecular defect.

    PubMed

    Fassihi, Hiva; Sethi, Mieran; Fawcett, Heather; Wing, Jonathan; Chandler, Natalie; Mohammed, Shehla; Craythorne, Emma; Morley, Ana M S; Lim, Rongxuan; Turner, Sally; Henshaw, Tanya; Garrood, Isabel; Giunti, Paola; Hedderly, Tammy; Abiona, Adesoji; Naik, Harsha; Harrop, Gemma; McGibbon, David; Jaspers, Nicolaas G J; Botta, Elena; Nardo, Tiziana; Stefanini, Miria; Young, Antony R; Sarkany, Robert P E; Lehmann, Alan R

    2016-03-01

    Xeroderma pigmentosum (XP) is a rare DNA repair disorder characterized by increased susceptibility to UV radiation (UVR)-induced skin pigmentation, skin cancers, ocular surface disease, and, in some patients, sunburn and neurological degeneration. Genetically, it is assigned to eight complementation groups (XP-A to -G and variant). For the last 5 y, the UK national multidisciplinary XP service has provided follow-up for 89 XP patients, representing most of the XP patients in the United Kingdom. Causative mutations, DNA repair levels, and more than 60 clinical variables relating to dermatology, ophthalmology, and neurology have been measured, using scoring systems to categorize disease severity. This deep phenotyping has revealed unanticipated heterogeneity of clinical features, between and within complementation groups. Skin cancer is most common in XP-C, XP-E, and XP-V patients, previously considered to be the milder groups based on cellular analyses. These patients have normal sunburn reactions and are therefore diagnosed later and are less likely to adhere to UVR protection. XP-C patients are specifically hypersensitive to ocular damage, and XP-F and XP-G patients appear to be much less susceptible to skin cancer than other XP groups. Within XP groups, different mutations confer susceptibility or resistance to neurological damage. Our findings on this large cohort of XP patients under long-term follow-up reveal that XP is more heterogeneous than has previously been appreciated. Our data now enable provision of personalized prognostic information and management advice for each XP patient, as well as providing new insights into the functions of the XP proteins.

  18. In situ TEM straining of nanograined free-standing thin films reveals various unexpected deformation mechanisms.

    SciTech Connect

    Follstaedt, David Martin; Knapp, James Arthur; Clark, Blythe G.; Hattar, Khalid M.; Robertson, Ian M.

    2010-04-01

    In-situ transmission electron microscopy (TEM) straining experiments provide direct detailed observation of the deformation and failure mechanisms active at a length scale relevant to nanomaterials. This presentation will detail continued investigations into the active mechanisms governing high purity nanograined pulsed-laser deposited (PLD) nickel, as well as recent work into dislocation-particle interactions in nanostructured PLD aluminum-alumina alloys. Straining experiments performed on nanograined PLD free-standing nanograined Ni films with an engineered grain size distribution revealed that the addition of ductility with limited decrease in strength, reported in such metals, can be attributed to the simultaneous activity of three deformation mechanisms in front of the crack tip. At the crack tip, a grain agglomeration mechanism occurs where several nanograins appear to rotate, resulting in a very thin, larger grain immediately prior to failure. In the classical plastic zone in front of the crack tip, a multitude of mechanisms were found to operate in the larger grains including: dislocation pile-up, twinning, and stress-assisted grain growth. The region outside of the plastic zone showed signs of elasticity with limited indications of dislocation activity. The insight gained from in-situ TEM straining experiments of nanograined PLD Ni provides feedback for models of the deformation and failure in nanograined FCC metals, and suggests a greater complexity in the active mechanisms. The investigation into the deformation and failure mechanisms of FCC metals via in-situ TEM straining experiments has been expanded to the effect of hard particles on the active mechanisms in nanograined aluminum with alumina particles. The microstructures investigated were developed with varying composition, grain size, and particle distribution via tailoring of the PLD conditions and subsequent annealing. In order to develop microstructures suitable for in-situ deformation testing

  19. Uranus' Southern Circulation Revealed by Voyager-2 Images: Asymmetric, Unique, Unexpected

    NASA Astrophysics Data System (ADS)

    Karkoschka, Erich

    2014-11-01

    The southern half of Uranus' southern hemisphere of Uranus has been exceptionally bland. Only a single discrete feature was detected in Voyager-2 images, and none has been seen in thousands of HST and ground-based images since. All other observed regions on Uranus and jovian planets have many features that defined circulation patterns of the jovian planets, but the circulation of Uranus south of -45 deg latitude has been unknown.We performed a reanalysis of Voyager images of Uranus that revealed dozens of discrete features instead of the single feature known before. We improved flatfielding, pad-pixel treatment, and nonlinearity correction. We greatly decreased noise by averaging up to 1600 images. The result is a rotational profile without major gaps.Uranus' high southern latitudes are exceptional in several aspects: 1) The rotational profile has sharp kinks while it is smooth elsewhere on the ice giants. This puts current ideas of a simple Hadley cell on each hemisphere into question. 2) The rotational profile has a large north-south asymmetry, an order of magnitude larger than elsewhere on the jovian planets. 3) Between -68 and -59 deg latitude, the rotational shear is some 30 times lower than at other latitudes. Here, winds speeds around 200 m/s are regular to the 0.1 m/s level. 4) The South Pole had a spot off center rotating 5 h faster than the interior, which has not been observed elsewhere on jovian planets. 5) Uranus revealed spirals winding around the whole planet more than once that indicate very regular meridional motions, to the 2 cm/s level. 6) The latitude at -84 deg was featureless even at a signal-to-noise ratio of 55,000, one of the blandest zones in nature.Some features show significant evolution within the 5-week observing period providing constraints on dynamics. Features also show distinct spectral characteristics in the 8-filter data set providing constraints on the physical nature of features and their altitude. We have the data to

  20. The structure of sperm Izumo1 reveals unexpected similarities with Plasmodium invasion proteins.

    PubMed

    Nishimura, Kaoru; Han, Ling; Bianchi, Enrica; Wright, Gavin J; de Sanctis, Daniele; Jovine, Luca

    2016-07-25

    Fertilization, the culminating event in sexual reproduction, occurs when haploid sperm and egg recognize each other and fuse to form a diploid zygote. In mammals this process critically depends on the interaction between Izumo1, a protein exposed on the equatorial segment of acrosome-reacted sperm, and the egg plasma-membrane-anchored receptor Juno [1,2]. The molecular mechanism triggering gamete fusion is unresolved because both Izumo1 and Juno lack sequence similarity to known membrane fusogens. Here we report the crystal structure of Izumo1, which reveals a membrane distal region composed of a four-helix bundle connected to a carboxy-terminal immunoglobulin (Ig)-like domain through a β-hairpin stabilized by disulfide bonds. Remarkably, different regions of Izumo1 display significant structural similarities to two proteins expressed by the invasive sporozoite stage of Plasmodium parasites: SPECT1, which is essential for host cell traversal and hepatocyte invasion [3]; and TRAP, which is necessary for gliding motility and invasion [4]. These observations suggest a link between the molecular mechanisms underlying host cell invasion by the malaria parasite and gamete membrane fusion at fertilization.

  1. Integrated analyses resolve conflicts over squamate reptile phylogeny and reveal unexpected placements for fossil taxa.

    PubMed

    Reeder, Tod W; Townsend, Ted M; Mulcahy, Daniel G; Noonan, Brice P; Wood, Perry L; Sites, Jack W; Wiens, John J

    2015-01-01

    Squamate reptiles (lizards and snakes) are a pivotal group whose relationships have become increasingly controversial. Squamates include >9000 species, making them the second largest group of terrestrial vertebrates. They are important medicinally and as model systems for ecological and evolutionary research. However, studies of squamate biology are hindered by uncertainty over their relationships, and some consider squamate phylogeny unresolved, given recent conflicts between molecular and morphological results. To resolve these conflicts, we expand existing morphological and molecular datasets for squamates (691 morphological characters and 46 genes, for 161 living and 49 fossil taxa, including a new set of 81 morphological characters and adding two genes from published studies) and perform integrated analyses. Our results resolve higher-level relationships as indicated by molecular analyses, and reveal hidden morphological support for the molecular hypothesis (but not vice-versa). Furthermore, we find that integrating molecular, morphological, and paleontological data leads to surprising placements for two major fossil clades (Mosasauria and Polyglyphanodontia). These results further demonstrate the importance of combining fossil and molecular information, and the potential problems of estimating the placement of fossil taxa from morphological data alone. Thus, our results caution against estimating fossil relationships without considering relevant molecular data, and against placing fossils into molecular trees (e.g. for dating analyses) without considering the possible impact of molecular data on their placement.

  2. Morphology and Molecules Reveal Unexpected Cryptic Diversity in the Enigmatic Genus Sinobirma Bryk, 1944 (Lepidoptera: Saturniidae)

    PubMed Central

    Rougerie, Rodolphe; Naumann, Stefan; Nässig, Wolfgang A.

    2012-01-01

    The wild silkmoth genus Sinobirma Bryk, 1944 is a poorly known monotypic taxon from the eastern end of the Himalaya Range. It was convincingly proposed to be closely related to some members of an exclusively Afro-tropical group of Saturniidae, but its biogeographical and evolutionary history remains enigmatic. After examining recently collected material from Tibet, northern India, and northeastern Myanmar, we realized that this unique species, S. malaisei Bryk, 1944 only known so far from a few specimens and from a very restricted area near the border between north-eastern Myanmar and the Yunnan province of China, may in fact belong to a group of closely related cryptic species. In this work, we combined morphological comparative study, DNA barcoding, and the sequences of a nuclear marker (D2 expansion segment of the 28S rRNA gene) to unequivocally delimit three distinct species in the genus Sinobirma, of which two are described as new to science: S. myanmarensis sp. n. and S. bouyeri sp. n. An informative DNA barcode sequence was obtained from the female holotype of S. malaisei—collected in 1934—ensuring the proper assignation of this name to the newly collected and studied specimens. Our findings represent another example of the potential of coupling traditional taxonomy and DNA barcoding for revealing and solving difficult cases of cryptic diversity. This approach is now being generalized to the world fauna of Saturniidae, with the participation of most of the taxonomists studying these moths. PMID:23028478

  3. Metagenomic investigation of the geologically unique Hellenic Volcanic Arc reveals a distinctive ecosystem with unexpected physiology.

    PubMed

    Oulas, Anastasis; Polymenakou, Paraskevi N; Seshadri, Rekha; Tripp, H James; Mandalakis, Manolis; Paez-Espino, A David; Pati, Amrita; Chain, Patrick; Nomikou, Paraskevi; Carey, Steven; Kilias, Stephanos; Christakis, Christos; Kotoulas, Georgios; Magoulas, Antonios; Ivanova, Natalia N; Kyrpides, Nikos C

    2016-04-01

    Hydrothermal vents represent a deep, hot, aphotic biosphere where chemosynthetic primary producers, fuelled by chemicals from Earth's subsurface, form the basis of life. In this study, we examined microbial mats from two distinct volcanic sites within the Hellenic Volcanic Arc (HVA). The HVA is geologically and ecologically unique, with reported emissions of CO2 -saturated fluids at temperatures up to 220°C and a notable absence of macrofauna. Metagenomic data reveals highly complex prokaryotic communities composed of chemolithoautotrophs, some methanotrophs, and to our surprise, heterotrophs capable of anaerobic degradation of aromatic hydrocarbons. Our data suggest that aromatic hydrocarbons may indeed be a significant source of carbon in these sites, and instigate additional research into the nature and origin of these compounds in the HVA. Novel physiology was assigned to several uncultured prokaryotic lineages; most notably, a SAR406 representative is attributed with a role in anaerobic hydrocarbon degradation. This dataset, the largest to date from submarine volcanic ecosystems, constitutes a significant resource of novel genes and pathways with potential biotechnological applications. PMID:26487573

  4. Common and unexpected findings in mummies from ancient Egypt and South America as revealed by CT.

    PubMed

    Jackowski, Christian; Bolliger, Stephan; Thali, Michael J

    2008-01-01

    Computed tomography (CT) has proved to be a valuable investigative tool for mummy research and is the method of choice for examining mummies. It allows for noninvasive insight, especially with virtual endoscopy, which reveals detailed information about the mummy's sex, age, constitution, injuries, health, and mummification techniques used. CT also supplies three-dimensional information about the scanned object. Mummification processes can be summarized as "artificial," when the procedure was performed on a body with the aim of preservation, or as "natural," when the body's natural environment resulted in preservation. The purpose of artificial mummification was to preserve that person's morphologic features by delaying or arresting the decay of the body. The ancient Egyptians are most famous for this. Their use of evisceration followed by desiccation with natron (a compound of sodium salts) to halt putrefaction and prevent rehydration was so effective that their embalmed bodies have survived for nearly 4500 years. First, the body was cleaned with a natron solution; then internal organs were removed through the cribriform plate and abdomen. The most important, and probably the most lengthy, phase was desiccation. After the body was dehydrated, the body cavities were rinsed and packed to restore the body's former shape. Finally, the body was wrapped. Animals were also mummified to provide food for the deceased, to accompany the deceased as pets, because they were seen as corporal manifestations of deities, and as votive offerings. Artificial mummification was performed on every continent, especially in South and Central America.

  5. Proteomic Investigation of Aphid Honeydew Reveals an Unexpected Diversity of Proteins

    PubMed Central

    Haubruge, Eric; Hance, Thierry; Thonart, Philippe; De Pauw, Edwin; Francis, Frédéric

    2013-01-01

    Aphids feed on the phloem sap of plants, and are the most common honeydew-producing insects. While aphid honeydew is primarily considered to comprise sugars and amino acids, its protein diversity has yet to be documented. Here, we report on the investigation of the honeydew proteome from the pea aphid Acyrthosiphon pisum. Using a two-Dimensional Differential in-Gel Electrophoresis (2D-Dige) approach, more than 140 spots were isolated, demonstrating that aphid honeydew also represents a diverse source of proteins. About 66% of the isolated spots were identified through mass spectrometry analysis, revealing that the protein diversity of aphid honeydew originates from several organisms (i.e. the host aphid and its microbiota, including endosymbiotic bacteria and gut flora). Interestingly, our experiments also allowed to identify some proteins like chaperonin, GroEL and Dnak chaperones, elongation factor Tu (EF-Tu), and flagellin that might act as mediators in the plant-aphid interaction. In addition to providing the first aphid honeydew proteome analysis, we propose to reconsider the importance of this substance, mainly acknowledged to be a waste product, from the aphid ecology perspective. PMID:24086359

  6. Integrated Analyses Resolve Conflicts over Squamate Reptile Phylogeny and Reveal Unexpected Placements for Fossil Taxa

    PubMed Central

    Reeder, Tod W.; Townsend, Ted M.; Mulcahy, Daniel G.; Noonan, Brice P.; Wood, Perry L.; Sites, Jack W.; Wiens, John J.

    2015-01-01

    Squamate reptiles (lizards and snakes) are a pivotal group whose relationships have become increasingly controversial. Squamates include >9000 species, making them the second largest group of terrestrial vertebrates. They are important medicinally and as model systems for ecological and evolutionary research. However, studies of squamate biology are hindered by uncertainty over their relationships, and some consider squamate phylogeny unresolved, given recent conflicts between molecular and morphological results. To resolve these conflicts, we expand existing morphological and molecular datasets for squamates (691 morphological characters and 46 genes, for 161 living and 49 fossil taxa, including a new set of 81 morphological characters and adding two genes from published studies) and perform integrated analyses. Our results resolve higher-level relationships as indicated by molecular analyses, and reveal hidden morphological support for the molecular hypothesis (but not vice-versa). Furthermore, we find that integrating molecular, morphological, and paleontological data leads to surprising placements for two major fossil clades (Mosasauria and Polyglyphanodontia). These results further demonstrate the importance of combining fossil and molecular information, and the potential problems of estimating the placement of fossil taxa from morphological data alone. Thus, our results caution against estimating fossil relationships without considering relevant molecular data, and against placing fossils into molecular trees (e.g. for dating analyses) without considering the possible impact of molecular data on their placement. PMID:25803280

  7. The structure of sperm Izumo1 reveals unexpected similarities with Plasmodium invasion proteins.

    PubMed

    Nishimura, Kaoru; Han, Ling; Bianchi, Enrica; Wright, Gavin J; de Sanctis, Daniele; Jovine, Luca

    2016-07-25

    Fertilization, the culminating event in sexual reproduction, occurs when haploid sperm and egg recognize each other and fuse to form a diploid zygote. In mammals this process critically depends on the interaction between Izumo1, a protein exposed on the equatorial segment of acrosome-reacted sperm, and the egg plasma-membrane-anchored receptor Juno [1,2]. The molecular mechanism triggering gamete fusion is unresolved because both Izumo1 and Juno lack sequence similarity to known membrane fusogens. Here we report the crystal structure of Izumo1, which reveals a membrane distal region composed of a four-helix bundle connected to a carboxy-terminal immunoglobulin (Ig)-like domain through a β-hairpin stabilized by disulfide bonds. Remarkably, different regions of Izumo1 display significant structural similarities to two proteins expressed by the invasive sporozoite stage of Plasmodium parasites: SPECT1, which is essential for host cell traversal and hepatocyte invasion [3]; and TRAP, which is necessary for gliding motility and invasion [4]. These observations suggest a link between the molecular mechanisms underlying host cell invasion by the malaria parasite and gamete membrane fusion at fertilization. PMID:27374339

  8. Metagenomic investigation of the geologically unique Hellenic Volcanic Arc reveals a distinctive ecosystem with unexpected physiology.

    PubMed

    Oulas, Anastasis; Polymenakou, Paraskevi N; Seshadri, Rekha; Tripp, H James; Mandalakis, Manolis; Paez-Espino, A David; Pati, Amrita; Chain, Patrick; Nomikou, Paraskevi; Carey, Steven; Kilias, Stephanos; Christakis, Christos; Kotoulas, Georgios; Magoulas, Antonios; Ivanova, Natalia N; Kyrpides, Nikos C

    2016-04-01

    Hydrothermal vents represent a deep, hot, aphotic biosphere where chemosynthetic primary producers, fuelled by chemicals from Earth's subsurface, form the basis of life. In this study, we examined microbial mats from two distinct volcanic sites within the Hellenic Volcanic Arc (HVA). The HVA is geologically and ecologically unique, with reported emissions of CO2 -saturated fluids at temperatures up to 220°C and a notable absence of macrofauna. Metagenomic data reveals highly complex prokaryotic communities composed of chemolithoautotrophs, some methanotrophs, and to our surprise, heterotrophs capable of anaerobic degradation of aromatic hydrocarbons. Our data suggest that aromatic hydrocarbons may indeed be a significant source of carbon in these sites, and instigate additional research into the nature and origin of these compounds in the HVA. Novel physiology was assigned to several uncultured prokaryotic lineages; most notably, a SAR406 representative is attributed with a role in anaerobic hydrocarbon degradation. This dataset, the largest to date from submarine volcanic ecosystems, constitutes a significant resource of novel genes and pathways with potential biotechnological applications.

  9. Expression of secreted Wnt pathway components reveals unexpected complexity of the planarian amputation response

    PubMed Central

    Gurley, Kyle A.; Elliott, Sarah A.; Simakov, Oleg; Schmidt, Heiko A.; Holstein, Thomas W.; Sánchez Alvarado, Alejandro

    2010-01-01

    Regeneration is widespread throughout the animal kingdom, but our molecular understanding of this process in adult animals remains poorly understood. Wnt/β-catenin signaling plays crucial roles throughout animal life from early development to adulthood. In intact and regenerating planarians, the regulation of Wnt/β-catenin signaling functions to maintain and specify anterior/posterior (A/P) identity. Here, we explore the expression kinetics and RNAi phenotypes for secreted members of the Wnt signaling pathway in the planarian Schmidtea mediterranea. Smed-wnt and sFRP expression during regeneration is surprisingly dynamic and reveals fundamental aspects of planarian biology that have been previously unappreciated. We show that after amputation, a wounding response precedes rapid reorganization of the A/P axis. Furthermore, cells throughout the body plan can mount this response and reassess their new A/P location in the complete absence of stem cells. While initial stages of the amputation response are stem cell independent, tissue remodeling and the integration of new A/P address with anatomy are stem cell dependent. We also show that WNT5 functions in a reciprocal manner with SLIT to pattern the planarian mediolateral axis, while WNT11-2 patterns the posterior midline. Moreover, we perform an extensive phylogenetic analysis on the Smed-wnt genes using a method that combines and integrates both sequence and structural alignments, enabling us to place all nine genes into Wnt subfamilies for the first time. PMID:20707997

  10. The Crystal Structure of Cancer Osaka Thyroid Kinase Reveals an Unexpected Kinase Domain Fold*

    PubMed Central

    Gutmann, Sascha; Hinniger, Alexandra; Fendrich, Gabriele; Drückes, Peter; Antz, Sylvie; Mattes, Henri; Möbitz, Henrik; Ofner, Silvio; Schmiedeberg, Niko; Stojanovic, Aleksandar; Rieffel, Sebastien; Strauss, André; Troxler, Thomas; Glatthar, Ralf; Sparrer, Helmut

    2015-01-01

    Macrophages are important cellular effectors in innate immune responses and play a major role in autoimmune diseases such as rheumatoid arthritis. Cancer Osaka thyroid (COT) kinase, also known as mitogen-activated protein kinase kinase kinase 8 (MAP3K8) and tumor progression locus 2 (Tpl-2), is a serine-threonine (ST) kinase and is a key regulator in the production of pro-inflammatory cytokines in macrophages. Due to its pivotal role in immune biology, COT kinase has been identified as an attractive target for pharmaceutical research that is directed at the discovery of orally available, selective, and potent inhibitors for the treatment of autoimmune disorders and cancer. The production of monomeric, recombinant COT kinase has proven to be very difficult, and issues with solubility and stability of the enzyme have hampered the discovery and optimization of potent and selective inhibitors. We developed a protocol for the production of recombinant human COT kinase that yields pure and highly active enzyme in sufficient yields for biochemical and structural studies. The quality of the enzyme allowed us to establish a robust in vitro phosphorylation assay for the efficient biochemical characterization of COT kinase inhibitors and to determine the x-ray co-crystal structures of the COT kinase domain in complex with two ATP-binding site inhibitors. The structures presented in this study reveal two distinct ligand binding modes and a unique kinase domain architecture that has not been observed previously. The structurally versatile active site significantly impacts the design of potent, low molecular weight COT kinase inhibitors. PMID:25918157

  11. The Crystal Structure of Cancer Osaka Thyroid Kinase Reveals an Unexpected Kinase Domain Fold.

    PubMed

    Gutmann, Sascha; Hinniger, Alexandra; Fendrich, Gabriele; Drückes, Peter; Antz, Sylvie; Mattes, Henri; Möbitz, Henrik; Ofner, Silvio; Schmiedeberg, Niko; Stojanovic, Aleksandar; Rieffel, Sebastien; Strauss, André; Troxler, Thomas; Glatthar, Ralf; Sparrer, Helmut

    2015-06-12

    Macrophages are important cellular effectors in innate immune responses and play a major role in autoimmune diseases such as rheumatoid arthritis. Cancer Osaka thyroid (COT) kinase, also known as mitogen-activated protein kinase kinase kinase 8 (MAP3K8) and tumor progression locus 2 (Tpl-2), is a serine-threonine (ST) kinase and is a key regulator in the production of pro-inflammatory cytokines in macrophages. Due to its pivotal role in immune biology, COT kinase has been identified as an attractive target for pharmaceutical research that is directed at the discovery of orally available, selective, and potent inhibitors for the treatment of autoimmune disorders and cancer. The production of monomeric, recombinant COT kinase has proven to be very difficult, and issues with solubility and stability of the enzyme have hampered the discovery and optimization of potent and selective inhibitors. We developed a protocol for the production of recombinant human COT kinase that yields pure and highly active enzyme in sufficient yields for biochemical and structural studies. The quality of the enzyme allowed us to establish a robust in vitro phosphorylation assay for the efficient biochemical characterization of COT kinase inhibitors and to determine the x-ray co-crystal structures of the COT kinase domain in complex with two ATP-binding site inhibitors. The structures presented in this study reveal two distinct ligand binding modes and a unique kinase domain architecture that has not been observed previously. The structurally versatile active site significantly impacts the design of potent, low molecular weight COT kinase inhibitors.

  12. Comparative transcriptomics of two environmentally relevant cyanobacteria reveals unexpected transcriptome diversity

    PubMed Central

    Voigt, Karsten; Sharma, Cynthia M; Mitschke, Jan; Joke Lambrecht, S; Voß, Björn; Hess, Wolfgang R; Steglich, Claudia

    2014-01-01

    Prochlorococcus is a genus of abundant and ecologically important marine cyanobacteria. Here, we present a comprehensive comparison of the structure and composition of the transcriptomes of two Prochlorococcus strains, which, despite their similarities, have adapted their gene pool to specific environmental constraints. We present genome-wide maps of transcriptional start sites (TSS) for both organisms, which are representatives of the two most diverse clades within the two major ecotypes adapted to high- and low-light conditions, respectively. Our data suggest antisense transcription for three-quarters of all genes, which is substantially more than that observed in other bacteria. We discovered hundreds of TSS within genes, most notably within 16 of the 29 prochlorosin genes, in strain MIT9313. A direct comparison revealed very little conservation in the location of TSS and the nature of non-coding transcripts between both strains. We detected extremely short 5′ untranslated regions with a median length of only 27 and 29 nt for MED4 and MIT9313, respectively, and for 8% of all protein-coding genes the median distance to the start codon is only 10 nt or even shorter. These findings and the absence of an obvious Shine–Dalgarno motif suggest that leaderless translation and ribosomal protein S1-dependent translation constitute alternative mechanisms for translation initiation in Prochlorococcus. We conclude that genome-wide antisense transcription is a major component of the transcriptional output from these relatively small genomes and that a hitherto unrecognized high degree of complexity and variability of gene expression exists in their transcriptional architecture. PMID:24739626

  13. Health, Happiness and Human Enhancement-Dealing with Unexpected Effects of Deep Brain Stimulation.

    PubMed

    Schermer, Maartje

    2013-01-01

    Deep Brain Stimulation (DBS) is a treatment involving the implantation of electrodes into the brain. Presently, it is used for neurological disorders like Parkinson's disease, but indications are expanding to psychiatric disorders such as depression, addiction and Obsessive Compulsive Disorder (OCD). Theoretically, it may be possible to use DBS for the enhancement of various mental functions. This article discusses a case of an OCD patient who felt very happy with the DBS treatment, even though her symptoms were not reduced. First, it is explored if the argument that 'doctors are not in the business of trading happiness', as used by her psychiatrist to justify his discontinuation of the DBS treatment, holds. The relationship between enhancement and the goals of medicine is discussed and it is concluded that even though the goals of medicine do not set strict limits and may even include certain types of enhancement, there are some good reasons for limiting the kind of things doctors are required or allowed to do. Next, the case is discussed from the perspective of beneficence and autonomy. It is argued that making people feel good is not the same as enhancing their well-being and that it is unlikely-though not absolutely impossible-that the well-being of the happy OCD patient is really improved. Finally, some concerns regarding the autonomy of a request made under the influence of DBS treatment are considered. PMID:24273618

  14. Health, Happiness and Human Enhancement-Dealing with Unexpected Effects of Deep Brain Stimulation.

    PubMed

    Schermer, Maartje

    2013-01-01

    Deep Brain Stimulation (DBS) is a treatment involving the implantation of electrodes into the brain. Presently, it is used for neurological disorders like Parkinson's disease, but indications are expanding to psychiatric disorders such as depression, addiction and Obsessive Compulsive Disorder (OCD). Theoretically, it may be possible to use DBS for the enhancement of various mental functions. This article discusses a case of an OCD patient who felt very happy with the DBS treatment, even though her symptoms were not reduced. First, it is explored if the argument that 'doctors are not in the business of trading happiness', as used by her psychiatrist to justify his discontinuation of the DBS treatment, holds. The relationship between enhancement and the goals of medicine is discussed and it is concluded that even though the goals of medicine do not set strict limits and may even include certain types of enhancement, there are some good reasons for limiting the kind of things doctors are required or allowed to do. Next, the case is discussed from the perspective of beneficence and autonomy. It is argued that making people feel good is not the same as enhancing their well-being and that it is unlikely-though not absolutely impossible-that the well-being of the happy OCD patient is really improved. Finally, some concerns regarding the autonomy of a request made under the influence of DBS treatment are considered.

  15. High-throughput sequencing-based analysis of endogenetic fungal communities inhabiting the Chinese Cordyceps reveals unexpectedly high fungal diversity

    PubMed Central

    Xia, Fei; Chen, Xin; Guo, Meng-Yuan; Bai, Xiao-Hui; Liu, Yan; Shen, Guang-Rong; Li, Yu-Ling; Lin, Juan; Zhou, Xuan-Wei

    2016-01-01

    Chinese Cordyceps, known in Chinese as “DongChong XiaCao”, is a parasitic complex of a fungus (Ophiocordyceps sinensis) and a caterpillar. The current study explored the endogenetic fungal communities inhabiting Chinese Cordyceps. Samples were collected from five different geographical regions of Qinghai and Tibet, and the nuclear ribosomal internal transcribed spacer-1 sequences from each sample were obtained using Illumina high-throughput sequencing. The results showed that Ascomycota was the dominant fungal phylum in Chinese Cordyceps and its soil microhabitat from different sampling regions. Among the Ascomycota, 65 genera were identified, and the abundant operational taxonomic units showed the strongest sequence similarity to Ophiocordyceps, Verticillium, Pseudallescheria, Candida and Ilyonectria Not surprisingly, the genus Ophiocordyceps was the largest among the fungal communities identified in the fruiting bodies and external mycelial cortices of Chinese Cordyceps. In addition, fungal communities in the soil microhabitats were clustered separately from the external mycelial cortices and fruiting bodies of Chinese Cordyceps from different sampling regions. There was no significant structural difference in the fungal communities between the fruiting bodies and external mycelial cortices of Chinese Cordyceps. This study revealed an unexpectedly high diversity of fungal communities inhabiting the Chinese Cordyceps and its microhabitats. PMID:27625176

  16. Post-genomic analyses of fungal lignocellulosic biomass degradation reveal the unexpected potential of the plant pathogen Ustilago maydis

    PubMed Central

    2012-01-01

    Background Filamentous fungi are potent biomass degraders due to their ability to thrive in ligno(hemi)cellulose-rich environments. During the last decade, fungal genome sequencing initiatives have yielded abundant information on the genes that are putatively involved in lignocellulose degradation. At present, additional experimental studies are essential to provide insights into the fungal secreted enzymatic pools involved in lignocellulose degradation. Results In this study, we performed a wide analysis of 20 filamentous fungi for which genomic data are available to investigate their biomass-hydrolysis potential. A comparison of fungal genomes and secretomes using enzyme activity profiling revealed discrepancies in carbohydrate active enzymes (CAZymes) sets dedicated to plant cell wall. Investigation of the contribution made by each secretome to the saccharification of wheat straw demonstrated that most of them individually supplemented the industrial Trichoderma reesei CL847 enzymatic cocktail. Unexpectedly, the most striking effect was obtained with the phytopathogen Ustilago maydis that improved the release of total sugars by 57% and of glucose by 22%. Proteomic analyses of the best-performing secretomes indicated a specific enzymatic mechanism of U. maydis that is likely to involve oxido-reductases and hemicellulases. Conclusion This study provides insight into the lignocellulose-degradation mechanisms by filamentous fungi and allows for the identification of a number of enzymes that are potentially useful to further improve the industrial lignocellulose bioconversion process. PMID:22300648

  17. High-throughput sequencing-based analysis of endogenetic fungal communities inhabiting the Chinese Cordyceps reveals unexpectedly high fungal diversity.

    PubMed

    Xia, Fei; Chen, Xin; Guo, Meng-Yuan; Bai, Xiao-Hui; Liu, Yan; Shen, Guang-Rong; Li, Yu-Ling; Lin, Juan; Zhou, Xuan-Wei

    2016-01-01

    Chinese Cordyceps, known in Chinese as "DongChong XiaCao", is a parasitic complex of a fungus (Ophiocordyceps sinensis) and a caterpillar. The current study explored the endogenetic fungal communities inhabiting Chinese Cordyceps. Samples were collected from five different geographical regions of Qinghai and Tibet, and the nuclear ribosomal internal transcribed spacer-1 sequences from each sample were obtained using Illumina high-throughput sequencing. The results showed that Ascomycota was the dominant fungal phylum in Chinese Cordyceps and its soil microhabitat from different sampling regions. Among the Ascomycota, 65 genera were identified, and the abundant operational taxonomic units showed the strongest sequence similarity to Ophiocordyceps, Verticillium, Pseudallescheria, Candida and Ilyonectria Not surprisingly, the genus Ophiocordyceps was the largest among the fungal communities identified in the fruiting bodies and external mycelial cortices of Chinese Cordyceps. In addition, fungal communities in the soil microhabitats were clustered separately from the external mycelial cortices and fruiting bodies of Chinese Cordyceps from different sampling regions. There was no significant structural difference in the fungal communities between the fruiting bodies and external mycelial cortices of Chinese Cordyceps. This study revealed an unexpectedly high diversity of fungal communities inhabiting the Chinese Cordyceps and its microhabitats. PMID:27625176

  18. Unexpected Genetic Diversity among and within Populations of the Toxic Dinoflagellate Alexandrium catenella as Revealed by Nuclear Microsatellite Markers▿

    PubMed Central

    Masseret, Estelle; Grzebyk, Daniel; Nagai, Satoshi; Genovesi, Benjamin; Lasserre, Bernard; Laabir, Mohamed; Collos, Yves; Vaquer, André; Berrebi, Patrick

    2009-01-01

    Since 1998, blooms of Alexandrium catenella associated with paralytic shellfish poisoning have been repeatedly reported for Thau Lagoon (French Mediterranean coast). Based on data obtained for rRNA gene markers, it has been suggested that the strains involved could be closely related to the Japanese temperate Asian ribotype of the temperate Asian clade. In order to gain more insight into the origin of these organisms, we carried out a genetic analysis of 61 Mediterranean and 23 Japanese strains using both ribosomal and microsatellite markers. Whereas the phylogeny based on ribosomal markers tended to confirm the previous findings, the analysis of microsatellite sequences revealed an unexpected distinction between the French and Japanese populations. This analysis also highlighted great intraspecific diversity that was not detected with the classical rRNA gene markers. The Japanese strains are divided into two differentiated A. catenella lineages: the Sea of Japan lineage and the east coast lineage, which includes populations from the Inland Sea and the Pacific Ocean. A. catenella strains isolated from Thau Lagoon belong to another lineage. These findings indicate that microsatellite markers are probably better suited to investigations of the population genetics of this species that is distributed worldwide. Finally, application of the population genetics concepts available for macroorganisms could support new paradigms for speciation and migration in phytoplankton assemblages. PMID:19201972

  19. Directed Evolution Reveals Unexpected Epistatic Interactions That Alter Metabolic Regulation and Enable Anaerobic Xylose Use by Saccharomyces cerevisiae

    PubMed Central

    Tremaine, Mary; Hebert, Alexander S.; Myers, Kevin S.; Sardi, Maria; Dickinson, Quinn; Reed, Jennifer L.; Zhang, Yaoping; Coon, Joshua J.; Hittinger, Chris Todd; Gasch, Audrey P.; Landick, Robert

    2016-01-01

    The inability of native Saccharomyces cerevisiae to convert xylose from plant biomass into biofuels remains a major challenge for the production of renewable bioenergy. Despite extensive knowledge of the regulatory networks controlling carbon metabolism in yeast, little is known about how to reprogram S. cerevisiae to ferment xylose at rates comparable to glucose. Here we combined genome sequencing, proteomic profiling, and metabolomic analyses to identify and characterize the responsible mutations in a series of evolved strains capable of metabolizing xylose aerobically or anaerobically. We report that rapid xylose conversion by engineered and evolved S. cerevisiae strains depends upon epistatic interactions among genes encoding a xylose reductase (GRE3), a component of MAP Kinase (MAPK) signaling (HOG1), a regulator of Protein Kinase A (PKA) signaling (IRA2), and a scaffolding protein for mitochondrial iron-sulfur (Fe-S) cluster biogenesis (ISU1). Interestingly, the mutation in IRA2 only impacted anaerobic xylose consumption and required the loss of ISU1 function, indicating a previously unknown connection between PKA signaling, Fe-S cluster biogenesis, and anaerobiosis. Proteomic and metabolomic comparisons revealed that the xylose-metabolizing mutant strains exhibit altered metabolic pathways relative to the parental strain when grown in xylose. Further analyses revealed that interacting mutations in HOG1 and ISU1 unexpectedly elevated mitochondrial respiratory proteins and enabled rapid aerobic respiration of xylose and other non-fermentable carbon substrates. Our findings suggest a surprising connection between Fe-S cluster biogenesis and signaling that facilitates aerobic respiration and anaerobic fermentation of xylose, underscoring how much remains unknown about the eukaryotic signaling systems that regulate carbon metabolism. PMID:27741250

  20. Novel and Unexpected Microbial Diversity in Acid Mine Drainage in Svalbard (78° N), Revealed by Culture-Independent Approaches

    PubMed Central

    García-Moyano, Antonio; Austnes, Andreas Erling; Lanzén, Anders; González-Toril, Elena; Aguilera, Ángeles; Øvreås, Lise

    2015-01-01

    Svalbard, situated in the high Arctic, is an important past and present coal mining area. Dozens of abandoned waste rock piles can be found in the proximity of Longyearbyen. This environment offers a unique opportunity for studying the biological control over the weathering of sulphide rocks at low temperatures. Although the extension and impact of acid mine drainage (AMD) in this area is known, the native microbial communities involved in this process are still scarcely studied and uncharacterized. Several abandoned mining areas were explored in the search for active AMD and a culture-independent approach was applied with samples from two different runoffs for the identification and quantification of the native microbial communities. The results obtained revealed two distinct microbial communities. One of the runoffs was more extreme with regards to pH and higher concentration of soluble iron and heavy metals. These conditions favored the development of algal-dominated microbial mats. Typical AMD microorganisms related to known iron-oxidizing bacteria (Acidithiobacillus ferrivorans, Acidobacteria and Actinobacteria) dominated the bacterial community although some unexpected populations related to Chloroflexi were also significant. No microbial mats were found in the second area. The geochemistry here showed less extreme drainage, most likely in direct contact with the ore under the waste pile. Large deposits of secondary minerals were found and the presence of iron stalks was revealed by microscopy analysis. Although typical AMD microorganisms were also detected here, the microbial community was dominated by other populations, some of them new to this type of system (Saccharibacteria, Gallionellaceae). These were absent or lowered in numbers the farther from the spring source and they could represent native populations involved in the oxidation of sulphide rocks within the waste rock pile. This environment appears thus as a highly interesting field of potential

  1. Novel and Unexpected Microbial Diversity in Acid Mine Drainage in Svalbard (78° N), Revealed by Culture-Independent Approaches

    PubMed Central

    García-Moyano, Antonio; Austnes, Andreas Erling; Lanzén, Anders; González-Toril, Elena; Aguilera, Ángeles; Øvreås, Lise

    2015-01-01

    Svalbard, situated in the high Arctic, is an important past and present coal mining area. Dozens of abandoned waste rock piles can be found in the proximity of Longyearbyen. This environment offers a unique opportunity for studying the biological control over the weathering of sulphide rocks at low temperatures. Although the extension and impact of acid mine drainage (AMD) in this area is known, the native microbial communities involved in this process are still scarcely studied and uncharacterized. Several abandoned mining areas were explored in the search for active AMD and a culture-independent approach was applied with samples from two different runoffs for the identification and quantification of the native microbial communities. The results obtained revealed two distinct microbial communities. One of the runoffs was more extreme with regards to pH and higher concentration of soluble iron and heavy metals. These conditions favored the development of algal-dominated microbial mats. Typical AMD microorganisms related to known iron-oxidizing bacteria (Acidithiobacillus ferrivorans, Acidobacteria and Actinobacteria) dominated the bacterial community although some unexpected populations related to Chloroflexi were also significant. No microbial mats were found in the second area. The geochemistry here showed less extreme drainage, most likely in direct contact with the ore under the waste pile. Large deposits of secondary minerals were found and the presence of iron stalks was revealed by microscopy analysis. Although typical AMD microorganisms were also detected here, the microbial community was dominated by other populations, some of them new to this type of system (Saccharibacteria, Gallionellaceae). These were absent or lowered in numbers the farther from the spring source and they could represent native populations involved in the oxidation of sulphide rocks within the waste rock pile. This environment appears thus as a highly interesting field of potential

  2. Novel and Unexpected Microbial Diversity in Acid Mine Drainage in Svalbard (78° N), Revealed by Culture-Independent Approaches.

    PubMed

    García-Moyano, Antonio; Austnes, Andreas Erling; Lanzén, Anders; González-Toril, Elena; Aguilera, Ángeles; Øvreås, Lise

    2015-10-13

    Svalbard, situated in the high Arctic, is an important past and present coal mining area. Dozens of abandoned waste rock piles can be found in the proximity of Longyearbyen. This environment offers a unique opportunity for studying the biological control over the weathering of sulphide rocks at low temperatures. Although the extension and impact of acid mine drainage (AMD) in this area is known, the native microbial communities involved in this process are still scarcely studied and uncharacterized. Several abandoned mining areas were explored in the search for active AMD and a culture-independent approach was applied with samples from two different runoffs for the identification and quantification of the native microbial communities. The results obtained revealed two distinct microbial communities. One of the runoffs was more extreme with regards to pH and higher concentration of soluble iron and heavy metals. These conditions favored the development of algal-dominated microbial mats. Typical AMD microorganisms related to known iron-oxidizing bacteria (Acidithiobacillus ferrivorans, Acidobacteria and Actinobacteria) dominated the bacterial community although some unexpected populations related to Chloroflexi were also significant. No microbial mats were found in the second area. The geochemistry here showed less extreme drainage, most likely in direct contact with the ore under the waste pile. Large deposits of secondary minerals were found and the presence of iron stalks was revealed by microscopy analysis. Although typical AMD microorganisms were also detected here, the microbial community was dominated by other populations, some of them new to this type of system (Saccharibacteria, Gallionellaceae). These were absent or lowered in numbers the farther from the spring source and they could represent native populations involved in the oxidation of sulphide rocks within the waste rock pile. This environment appears thus as a highly interesting field of potential

  3. Metatranscriptomic analysis of a high-sulfide aquatic spring reveals insights into sulfur cycling and unexpected aerobic metabolism

    PubMed Central

    Elshahed, Mostafa S.; Najar, Fares Z.; Krumholz, Lee R.

    2015-01-01

    Zodletone spring is a sulfide-rich spring in southwestern Oklahoma characterized by shallow, microoxic, light-exposed spring water overlaying anoxic sediments. Previously, culture-independent 16S rRNA gene based diversity surveys have revealed that Zodletone spring source sediments harbor a highly diverse microbial community, with multiple lineages putatively involved in various sulfur-cycling processes. Here, we conducted a metatranscriptomic survey of microbial populations in Zodletone spring source sediments to characterize the relative prevalence and importance of putative phototrophic, chemolithotrophic, and heterotrophic microorganisms in the sulfur cycle, the identity of lineages actively involved in various sulfur cycling processes, and the interaction between sulfur cycling and other geochemical processes at the spring source. Sediment samples at the spring’s source were taken at three different times within a 24-h period for geochemical analyses and RNA sequencing. In depth mining of datasets for sulfur cycling transcripts revealed major sulfur cycling pathways and taxa involved, including an unexpected potential role of Actinobacteria in sulfide oxidation and thiosulfate transformation. Surprisingly, transcripts coding for the cyanobacterial Photosystem II D1 protein, methane monooxygenase, and terminal cytochrome oxidases were encountered, indicating that genes for oxygen production and aerobic modes of metabolism are actively being transcribed, despite below-detectable levels (<1 µM) of oxygen in source sediment. Results highlight transcripts involved in sulfur, methane, and oxygen cycles, propose that oxygenic photosynthesis could support aerobic methane and sulfide oxidation in anoxic sediments exposed to sunlight, and provide a viewpoint of microbial metabolic lifestyles under conditions similar to those seen during late Archaean and Proterozoic eons. PMID:26417542

  4. Metatranscriptomic analysis of a high-sulfide aquatic spring reveals insights into sulfur cycling and unexpected aerobic metabolism.

    PubMed

    Spain, Anne M; Elshahed, Mostafa S; Najar, Fares Z; Krumholz, Lee R

    2015-01-01

    Zodletone spring is a sulfide-rich spring in southwestern Oklahoma characterized by shallow, microoxic, light-exposed spring water overlaying anoxic sediments. Previously, culture-independent 16S rRNA gene based diversity surveys have revealed that Zodletone spring source sediments harbor a highly diverse microbial community, with multiple lineages putatively involved in various sulfur-cycling processes. Here, we conducted a metatranscriptomic survey of microbial populations in Zodletone spring source sediments to characterize the relative prevalence and importance of putative phototrophic, chemolithotrophic, and heterotrophic microorganisms in the sulfur cycle, the identity of lineages actively involved in various sulfur cycling processes, and the interaction between sulfur cycling and other geochemical processes at the spring source. Sediment samples at the spring's source were taken at three different times within a 24-h period for geochemical analyses and RNA sequencing. In depth mining of datasets for sulfur cycling transcripts revealed major sulfur cycling pathways and taxa involved, including an unexpected potential role of Actinobacteria in sulfide oxidation and thiosulfate transformation. Surprisingly, transcripts coding for the cyanobacterial Photosystem II D1 protein, methane monooxygenase, and terminal cytochrome oxidases were encountered, indicating that genes for oxygen production and aerobic modes of metabolism are actively being transcribed, despite below-detectable levels (<1 µM) of oxygen in source sediment. Results highlight transcripts involved in sulfur, methane, and oxygen cycles, propose that oxygenic photosynthesis could support aerobic methane and sulfide oxidation in anoxic sediments exposed to sunlight, and provide a viewpoint of microbial metabolic lifestyles under conditions similar to those seen during late Archaean and Proterozoic eons. PMID:26417542

  5. Modeling and experiment reveal an unexpected stereoelectronic effect on conformation and scalar couplings of alpha-aminoorganostannanes, with possible relevance to the tin-lithium exchange reaction.

    PubMed

    Santiago, Marcelina; Low, Eddy; Chambournier, Gilles; Gawley, Robert E

    2003-10-31

    The solution conformation of N-methyl-2-(tributylstannyl)piperidines has been determined through the use of vicinal 119Sn-13C coupling constants, revealing a conformational distortion caused by an unexpected stereoelectronic effect in some cases. Specifically, the "equatorial" conformer is distorted into a half-chair, in which the nitrogen lone pair eclipses the C-Sn bond. This distortion, which "costs" approximately 1 kcal/mol, correlates with a conformational dependence of geminal 119Sn-15N couplings and a possible correlation with reactivity in the tin-lithium exchange reaction. PMID:14575474

  6. Modeling and experiment reveal an unexpected stereoelectronic effect on conformation and scalar couplings of alpha-aminoorganostannanes, with possible relevance to the tin-lithium exchange reaction.

    PubMed

    Santiago, Marcelina; Low, Eddy; Chambournier, Gilles; Gawley, Robert E

    2003-10-31

    The solution conformation of N-methyl-2-(tributylstannyl)piperidines has been determined through the use of vicinal 119Sn-13C coupling constants, revealing a conformational distortion caused by an unexpected stereoelectronic effect in some cases. Specifically, the "equatorial" conformer is distorted into a half-chair, in which the nitrogen lone pair eclipses the C-Sn bond. This distortion, which "costs" approximately 1 kcal/mol, correlates with a conformational dependence of geminal 119Sn-15N couplings and a possible correlation with reactivity in the tin-lithium exchange reaction.

  7. Second generation sequencing and morphological faecal analysis reveal unexpected foraging behaviour by Myotis nattereri (Chiroptera, Vespertilionidae) in winter

    PubMed Central

    2014-01-01

    Background Temperate winters produce extreme energetic challenges for small insectivorous mammals. Some bat species inhabiting locations with mild temperate winters forage during brief inter-torpor normothermic periods of activity. However, the winter diet of bats in mild temperate locations is studied infrequently. Although microscopic analyses of faeces have traditionally been used to characterise bat diet, recently the coupling of PCR with second generation sequencing has offered the potential to further advance our understanding of animal dietary composition and foraging behaviour by allowing identification of a much greater proportion of prey items often with increased taxonomic resolution. We used morphological analysis and Illumina-based second generation sequencing to study the winter diet of Natterer’s bat (Myotis nattereri) and compared the results obtained from these two approaches. For the first time, we demonstrate the applicability of the Illumina MiSeq platform as a data generation source for bat dietary analyses. Results Faecal pellets collected from a hibernation site in southern England during two winters (December-March 2009–10 and 2010–11), indicated that M. nattereri forages throughout winter at least in a location with a mild winter climate. Through morphological analysis, arthropod fragments from seven taxonomic orders were identified. A high proportion of these was non-volant (67.9% of faecal pellets) and unexpectedly included many lepidopteran larvae. Molecular analysis identified 43 prey species from six taxonomic orders and confirmed the frequent presence of lepidopteran species that overwinter as larvae. Conclusions The winter diet of M. nattereri is substantially different from other times of the year confirming that this species has a wide and adaptable dietary niche. Comparison of DNA derived from the prey to an extensive reference dataset of potential prey barcode sequences permitted fine scale taxonomic resolution of prey

  8. Bio-mimicking of Proline-Rich Motif Applied to Carbon Nanotube Reveals Unexpected Subtleties Underlying Nanoparticle Functionalization

    PubMed Central

    Zhang, Yuanzhao; Jimenez-Cruz, Camilo A.; Wang, Jian; Zhou, Bo; Yang, Zaixing; Zhou, Ruhong

    2014-01-01

    Here, we report computational studies of the SH3 protein domain interacting with various single-walled carbon nanotubes (SWCNT) either bare or functionalized by mimicking the proline-rich motif (PRM) ligand (PPPVPPRR) and compare it to the SH3-PRM complex binding. With prolines or a single arginine attached, the SWCNT gained slightly on specificity when compared with the bare control, whereas with multi-arginine systems the specificity dropped dramatically to our surprise. Although the electrostatic interaction provided by arginines is crucial in the recognition between PRM and SH3 domain, our results suggest that attaching multiple arginines to the SWCNT has a detrimental effect on the binding affinity. Detailed analysis of the MD trajectories found two main factors that modulate the specificity of the binding: the existence of competing acidic patches at the surface of SH3 that leads to “trapping and clamping” by the arginines, and the rigidity of the SWCNT introducing entropic penalties in the proper binding. Further investigation revealed that the same “clamping” phenomenon exits in the PRM-SH3 system, which has not been reported in previous literature. The competing effects between nanoparticle and its functionalization components revealed by our model system should be of value to current and future nanomedicine designs. PMID:25427563

  9. Culture-independent genome sequencing of clinical samples reveals an unexpected heterogeneity of infections by Chlamydia pecorum.

    PubMed

    Bachmann, Nathan L; Sullivan, Mitchell J; Jelocnik, Martina; Myers, Garry S A; Timms, Peter; Polkinghorne, Adam

    2015-05-01

    Chlamydia pecorum is an important global pathogen of livestock, and it is also a significant threat to the long-term survival of Australia's koala populations. This study employed a culture-independent DNA capture approach to sequence C. pecorum genomes directly from clinical swab samples collected from koalas with chlamydial disease as well as from sheep with arthritis and conjunctivitis. Investigations into single-nucleotide polymorphisms within each of the swab samples revealed that a portion of the reads in each sample belonged to separate C. pecorum strains, suggesting that all of the clinical samples analyzed contained mixed populations of genetically distinct C. pecorum isolates. This observation was independent of the anatomical site sampled and the host species. Using the genomes of strains identified in each of these samples, whole-genome phylogenetic analysis revealed that a clade containing a bovine and a koala isolate is distinct from other clades comprised of livestock or koala C. pecorum strains. Providing additional evidence to support exposure of koalas to Australian livestock strains, two minor strains assembled from the koala swab samples clustered with livestock strains rather than koala strains. Culture-independent probe-based genome capture and sequencing of clinical samples provides the strongest evidence yet to suggest that naturally occurring chlamydial infections are comprised of multiple genetically distinct strains. PMID:25740768

  10. Culture-independent genome sequencing of clinical samples reveals an unexpected heterogeneity of infections by Chlamydia pecorum.

    PubMed

    Bachmann, Nathan L; Sullivan, Mitchell J; Jelocnik, Martina; Myers, Garry S A; Timms, Peter; Polkinghorne, Adam

    2015-05-01

    Chlamydia pecorum is an important global pathogen of livestock, and it is also a significant threat to the long-term survival of Australia's koala populations. This study employed a culture-independent DNA capture approach to sequence C. pecorum genomes directly from clinical swab samples collected from koalas with chlamydial disease as well as from sheep with arthritis and conjunctivitis. Investigations into single-nucleotide polymorphisms within each of the swab samples revealed that a portion of the reads in each sample belonged to separate C. pecorum strains, suggesting that all of the clinical samples analyzed contained mixed populations of genetically distinct C. pecorum isolates. This observation was independent of the anatomical site sampled and the host species. Using the genomes of strains identified in each of these samples, whole-genome phylogenetic analysis revealed that a clade containing a bovine and a koala isolate is distinct from other clades comprised of livestock or koala C. pecorum strains. Providing additional evidence to support exposure of koalas to Australian livestock strains, two minor strains assembled from the koala swab samples clustered with livestock strains rather than koala strains. Culture-independent probe-based genome capture and sequencing of clinical samples provides the strongest evidence yet to suggest that naturally occurring chlamydial infections are comprised of multiple genetically distinct strains.

  11. Expression profiling reveals an unexpected growth-stimulating effect of surplus iron on the yeast Saccharomyces cerevisiae.

    PubMed

    Du, Yang; Cheng, Wang; Li, Wei-Fang

    2012-08-01

    Iron homeostasis plays a crucial role in growth and division of cells in all kingdoms of life. Although yeast iron metabolism has been extensively studied, little is known about the molecular mechanism of response to surplus iron. In this study, expression profiling of Saccharomyces cerevisiae in the presence of surplus iron revealed a dual effect at 1 and 4 h. A cluster of stress-responsive genes was upregulated via activation of the stress-resistance transcription factor Msn4, which indicated the stress effect of surplus iron on yeast metabolism. Genes involved in aerobic metabolism and several anabolic pathways are also upregulated in iron-surplus conditions, which could significantly accelerate yeast growth. This dual effect suggested that surplus iron might participate in a more complex metabolic network, in addition to serving as a stress inducer. These findings contribute to our understanding of the global response of yeast to the fluctuating availability of iron in the environment.

  12. Dissecting tRNA-derived fragment complexities using personalized transcriptomes reveals novel fragment classes and unexpected dependencies

    PubMed Central

    Telonis, Aristeidis G.; Loher, Phillipe; Honda, Shozo; Jing, Yi; Palazzo, Juan; Kirino, Yohei; Rigoutsos, Isidore

    2015-01-01

    We analyzed transcriptomic data from 452 healthy men and women representing five different human populations and two races, and, 311 breast cancer samples from The Cancer Genome Atlas. Our studies revealed numerous constitutive, distinct fragments with overlapping sequences and quantized lengths that persist across dozens of individuals and arise from the genomic loci of all nuclear and mitochondrial human transfer RNAs (tRNAs). Surprisingly, we discovered that the tRNA fragments' length, starting and ending points, and relative abundance depend on gender, population, race and also on amino acid identity, anticodon, genomic locus, tissue, disease, and disease subtype. Moreover, the length distribution of mitochondrially-encoded tRNAs differs from that of nuclearly-encoded tRNAs, and the specifics of these distributions depend on tissue. Notably, tRNA fragments from the same anticodon do not have correlated abundances. We also report on a novel category of tRNA fragments that significantly contribute to the differences we observe across tissues, genders, populations, and races: these fragments, referred to as i-tRFs, are abundant in human tissues, wholly internal to the respective mature tRNA, and can straddle the anticodon. HITS-CLIP data analysis revealed that tRNA fragments are loaded on Argonaute in a cell-dependent manner, suggesting cell-dependent functional roles through the RNA interference pathway. We validated experimentally two i-tRF molecules: the first was found in 21 of 22 tested breast tumor and adjacent normal samples and was differentially abundant between health and disease whereas the second was found in all eight tested breast cancer cell lines. PMID:26325506

  13. Detailed monitoring of a small but recovering population reveals sublethal effects of disease and unexpected interactions with supplemental feeding.

    PubMed

    Tollington, Simon; Greenwood, Andrew; Jones, Carl G; Hoeck, Paquita; Chowrimootoo, Aurélie; Smith, Donal; Richards, Heather; Tatayah, Vikash; Groombridge, Jim J

    2015-07-01

    Infectious diseases are widely recognized to have substantial impact on wildlife populations. These impacts are sometimes exacerbated in small endangered populations, and therefore, the success of conservation reintroductions to aid the recovery of such species can be seriously threatened by outbreaks of infectious disease. Intensive management strategies associated with conservation reintroductions can further compound these negative effects in such populations. Exploring the sublethal effects of disease outbreaks among natural populations is challenging and requires longitudinal, individual life-history data on patterns of reproductive success and other indicators of individual fitness. Long-term monitoring data concerning detailed reproductive information of the reintroduced Mauritius parakeet (Psittacula echo) population collected before, during and after a disease outbreak was investigated. Deleterious effects of an outbreak of beak and feather disease virus (BFDV) were revealed on hatch success, but these effects were remarkably short-lived and disproportionately associated with breeding pairs which took supplemental food. Individual BFDV infection status was not predicted by any genetic, environmental or conservation management factors and was not associated with any of our measures of immune function, perhaps suggesting immunological impairment. Experimental immunostimulation using the PHA (phytohaemagglutinin assay) challenge technique did, however, provoke a significant cellular immune response. We illustrate the resilience of this bottlenecked and once critically endangered, island-endemic species to an epidemic outbreak of BFDV and highlight the value of systematic monitoring in revealing inconspicuous but nonetheless substantial ecological interactions. Our study demonstrates that the emergence of such an infectious disease in a population ordinarily associated with increased susceptibility does not necessarily lead to deleterious impacts on population

  14. Multilocus phylogenetic analyses reveal unexpected abundant diversity and significant disjunct distribution pattern of the Hedgehog Mushrooms (Hydnum L.).

    PubMed

    Feng, Bang; Wang, Xiang-Hua; Ratkowsky, David; Gates, Genevieve; Lee, Su See; Grebenc, Tine; Yang, Zhu L

    2016-01-01

    Hydnum is a fungal genus proposed by Linnaeus in the early time of modern taxonomy. It contains several ectomycorrhizal species which are commonly consumed worldwide. However, Hydnum is one of the most understudied fungal genera, especially from a molecular phylogenetic view. In this study, we extensively gathered specimens of Hydnum from Asia, Europe, America and Australasia, and analyzed them by using sequences of four gene fragments (ITS, nrLSU, tef1α and rpb1). Our phylogenetic analyses recognized at least 31 phylogenetic species within Hydnum, 15 of which were reported for the first time. Most Australasian species were recognized as strongly divergent old relics, but recent migration between Australasia and the Northern Hemisphere was also detected. Within the Northern Hemisphere, frequent historical biota exchanges between the Old World and the New World via both the North Atlantic Land Bridge and the Bering Land Bridge could be elucidated. Our study also revealed that most Hydnum species found in subalpine areas of the Hengduan Mountains in southwestern China occur in northeastern/northern China and Europe, indicating that the composition of the mycobiota in the Hengduan Mountains reigion is more complicated than what we have known before. PMID:27151256

  15. Micro-CT scan reveals an unexpected high-volume and interconnected pore network in a Cretaceous Sanagasta dinosaur eggshell.

    PubMed

    Hechenleitner, E Martín; Grellet-Tinner, Gerald; Foley, Matthew; Fiorelli, Lucas E; Thompson, Michael B

    2016-03-01

    The Cretaceous Sanagasta neosauropod nesting site (La Rioja, Argentina) was the first confirmed instance of extinct dinosaurs using geothermal-generated heat to incubate their eggs. The nesting strategy and hydrothermal activities at this site led to the conclusion that the surprisingly 7 mm thick-shelled eggs were adapted to harsh hydrothermal microenvironments. We used micro-CT scans in this study to obtain the first three-dimensional microcharacterization of these eggshells. Micro-CT-based analyses provide a robust assessment of gas conductance in fossil dinosaur eggshells with complex pore canal systems, allowing calculation, for the first time, of the shell conductance through its thickness. This novel approach suggests that the shell conductance could have risen during incubation to seven times more than previously estimated as the eggshell erodes. In addition, micro-CT observations reveal that the constant widening and branching of pore canals form a complex funnel-like pore canal system. Furthermore, the high density of pore canals and the presence of a lateral canal network in the shell reduce the risks of pore obstruction during the extended incubation of these eggs in a relatively highly humid and muddy nesting environment. PMID:27009182

  16. Multilocus phylogenetic analyses reveal unexpected abundant diversity and significant disjunct distribution pattern of the Hedgehog Mushrooms (Hydnum L.)

    PubMed Central

    Feng, Bang; Wang, Xiang-Hua; Ratkowsky, David; Gates, Genevieve; Lee, Su See; Grebenc, Tine; Yang, Zhu L.

    2016-01-01

    Hydnum is a fungal genus proposed by Linnaeus in the early time of modern taxonomy. It contains several ectomycorrhizal species which are commonly consumed worldwide. However, Hydnum is one of the most understudied fungal genera, especially from a molecular phylogenetic view. In this study, we extensively gathered specimens of Hydnum from Asia, Europe, America and Australasia, and analyzed them by using sequences of four gene fragments (ITS, nrLSU, tef1α and rpb1). Our phylogenetic analyses recognized at least 31 phylogenetic species within Hydnum, 15 of which were reported for the first time. Most Australasian species were recognized as strongly divergent old relics, but recent migration between Australasia and the Northern Hemisphere was also detected. Within the Northern Hemisphere, frequent historical biota exchanges between the Old World and the New World via both the North Atlantic Land Bridge and the Bering Land Bridge could be elucidated. Our study also revealed that most Hydnum species found in subalpine areas of the Hengduan Mountains in southwestern China occur in northeastern/northern China and Europe, indicating that the composition of the mycobiota in the Hengduan Mountains reigion is more complicated than what we have known before. PMID:27151256

  17. Analysis of Two Putative Candida albicans Phosphopantothenoylcysteine Decarboxylase / Protein Phosphatase Z Regulatory Subunits Reveals an Unexpected Distribution of Functional Roles

    PubMed Central

    Petrényi, Katalin; Molero, Cristina; Kónya, Zoltán; Erdődi, Ferenc; Ariño, Joaquin; Dombrádi, Viktor

    2016-01-01

    Protein phosphatase Z (Ppz) is a fungus specific enzyme that regulates cell wall integrity, cation homeostasis and oxidative stress response. Work on Saccharomyces cerevisiae has shown that the enzyme is inhibited by Hal3/Vhs3 moonlighting proteins that together with Cab3 constitute the essential phosphopantothenoylcysteine decarboxylase (PPCDC) enzyme. In Candida albicans CaPpz1 is also involved in the morphological changes and infectiveness of this opportunistic human pathogen. To reveal the CaPpz1 regulatory context we searched the C. albicans database and identified two genes that, based on the structure of their S. cerevisiae counterparts, were termed CaHal3 and CaCab3. By pull down analysis and phosphatase assays we demonstrated that both of the bacterially expressed recombinant proteins were able to bind and inhibit CaPpz1 as well as its C-terminal catalytic domain (CaPpz1-Cter) with comparable efficiency. The binding and inhibition were always more pronounced with CaPpz1-Cter, indicating a protective effect against inhibition by the N-terminal domain in the full length protein. The functions of the C. albicans proteins were tested by their overexpression in S. cerevisiae. Contrary to expectations we found that only CaCab3 and not CaHal3 rescued the phenotypic traits that are related to phosphatase inhibition by ScHal3, such as tolerance to LiCl or hygromycin B, requirement for external K+ concentrations, or growth in a MAP kinase deficient slt2 background. On the other hand, both of the Candida proteins turned out to be essential PPCDC components and behaved as their S. cerevisiae counterparts: expression of CaCab3 and CaHal3 rescued the cab3 and hal3 vhs3 S. cerevisiae mutations, respectively. Thus, both CaHal3 and CaCab3 retained the PPCDC related functions and have the potential for CaPpz1 inhibition in vitro. The fact that only CaCab3 exhibits its phosphatase regulatory potential in vivo suggests that in C. albicans CaCab3, but not CaHal3, acts as a

  18. Analysis of Two Putative Candida albicans Phosphopantothenoylcysteine Decarboxylase / Protein Phosphatase Z Regulatory Subunits Reveals an Unexpected Distribution of Functional Roles.

    PubMed

    Petrényi, Katalin; Molero, Cristina; Kónya, Zoltán; Erdődi, Ferenc; Ariño, Joaquin; Dombrádi, Viktor

    2016-01-01

    Protein phosphatase Z (Ppz) is a fungus specific enzyme that regulates cell wall integrity, cation homeostasis and oxidative stress response. Work on Saccharomyces cerevisiae has shown that the enzyme is inhibited by Hal3/Vhs3 moonlighting proteins that together with Cab3 constitute the essential phosphopantothenoylcysteine decarboxylase (PPCDC) enzyme. In Candida albicans CaPpz1 is also involved in the morphological changes and infectiveness of this opportunistic human pathogen. To reveal the CaPpz1 regulatory context we searched the C. albicans database and identified two genes that, based on the structure of their S. cerevisiae counterparts, were termed CaHal3 and CaCab3. By pull down analysis and phosphatase assays we demonstrated that both of the bacterially expressed recombinant proteins were able to bind and inhibit CaPpz1 as well as its C-terminal catalytic domain (CaPpz1-Cter) with comparable efficiency. The binding and inhibition were always more pronounced with CaPpz1-Cter, indicating a protective effect against inhibition by the N-terminal domain in the full length protein. The functions of the C. albicans proteins were tested by their overexpression in S. cerevisiae. Contrary to expectations we found that only CaCab3 and not CaHal3 rescued the phenotypic traits that are related to phosphatase inhibition by ScHal3, such as tolerance to LiCl or hygromycin B, requirement for external K+ concentrations, or growth in a MAP kinase deficient slt2 background. On the other hand, both of the Candida proteins turned out to be essential PPCDC components and behaved as their S. cerevisiae counterparts: expression of CaCab3 and CaHal3 rescued the cab3 and hal3 vhs3 S. cerevisiae mutations, respectively. Thus, both CaHal3 and CaCab3 retained the PPCDC related functions and have the potential for CaPpz1 inhibition in vitro. The fact that only CaCab3 exhibits its phosphatase regulatory potential in vivo suggests that in C. albicans CaCab3, but not CaHal3, acts as a

  19. Unexpected effects of peripherally administered kynurenic acid on cortical spreading depression and related blood–brain barrier permeability

    PubMed Central

    Oláh, Gáspár; Herédi, Judit; Menyhárt, Ákos; Czinege, Zsolt; Nagy, Dávid; Fuzik, János; Kocsis, Kitti; Knapp, Levente; Krucsó, Erika; Gellért, Levente; Kis, Zsolt; Farkas, Tamás; Fülöp, Ferenc; Párdutz, Árpád; Tajti, János; Vécsei, László; Toldi, József

    2013-01-01

    Cortical spreading depression (CSD) involves a slowly-propagating depolarization wave in the cortex, which can appear in numerous pathophysiological conditions, such as migraine with aura, stroke, and traumatic brain injury. Neurons and glial cells are also depolarized transiently during the phenomena. CSD is followed by a massive increase in glutamate release and by changes in the brain microcirculation. The aim of this study was to investigate the effects of two N-methyl-D-aspartate receptor antagonists, endogenous kynurenic acid (KYNA) and dizocilpine, on CSD and the related blood–brain barrier (BBB) permeability in rats. In intact animals, KYNA hardly crosses the BBB but has some positive features as compared with its precursor L-Kynurenine, which is frequently used in animal studies (KYNA cannot be metabolized to excitotoxic agents such as 3-hydroxy-L-kynurenine and quinolinic acid). We therefore investigated the possible effects of peripherally administered KYNA. Repetitive CSD waves were elicited by the application of 1 M KCl solution to the cortex. Direct current-electrocorticograms were measured for 1 hour. Four parameters of the waves were compared. Evans blue dye and fluorescent microscopy were used to study the possible changes in the permeability of the BBB. The results demonstrated that N-methyl-D-aspartate receptor antagonists can reduce the number of CSD waves and decrease the permeability of the BBB during CSD. These results suggest that KYNA itself or its derivatives may offer a new approach in the therapy of migraines. PMID:24068867

  20. Crystal structure of Rab6A'(Q72L) mutant reveals unexpected GDP/Mg²⁺ binding with opened GTP-binding domain.

    PubMed

    Shin, Young-Cheul; Yoon, Jong Hwan; Jang, Tae-Ho; Kim, Seo Yun; Heo, Won Do; So, Insuk; Jeon, Ju-Hong; Park, Hyun Ho

    2012-07-27

    The Ras small G protein-superfamily is a family of GTP hydrolases whose activity is regulated by GTP/GDP binding states. Rab6A, a member of the Ras superfamily, is involved in the regulation of vesicle trafficking, which is critical for endocytosis, biosynthesis, secretion, cell differentiation and cell growth. Rab6A exists in two isoforms, termed RabA and Rab6A'. Substitution of Gln72 to Leu72 (Q72L) at Rab6 family blocks GTP hydrolysis activity and this mutation usually causes the Rab6 protein to be constitutively in an active form. Here, we report the crystal structure of the human Rab6A'(Q72L) mutant form at 1.9Å resolution. Unexpectedly, we found that Rab6A'(Q72L) possesses GDP/Mg(2+) in the GTP binding pockets, which is formed by a flexible switch I and switch II. Large conformational changes were also detected in the switch I and switch II regions. Our structure revealed that the non-hydrolysable, constitutively active form of Rab6A' can accommodate GDP/Mg(2+) in the open conformation.

  1. A study on the biosynthesis of hygrophorone B(12) in the mushroom Hygrophorus abieticola reveals an unexpected labelling pattern in the cyclopentenone moiety.

    PubMed

    Otto, Alexander; Porzel, Andrea; Schmidt, Jürgen; Wessjohann, Ludger; Arnold, Norbert

    2015-10-01

    The hitherto unknown natural formation of hygrophorones, antibacterial and antifungal cyclopentenone derivatives from mushrooms, was investigated for hygrophorone B(12) in Hygrophorus abieticola Krieglst. ex Gröger & Bresinsky by feeding experiments in the field using (13)C labelled samples of D-glucose and sodium acetate. The incorporation of (13)C isotopes was extensively studied using 1D and 2D NMR spectroscopy as well as ESI-HRMS analyses. In the experiment with [U-(13)C6]-glucose, six different (13)C2 labelled isotopomers were observed in the 2D INADEQUATE spectrum due to incorporation of [1,2-(13)C2]-acetyl-CoA. This labelling pattern demonstrated that hygrophorone B(12) is derived from a fatty acid-polyketide route instead of a 1,4-α-D-glucan derived anhydrofructose pathway. The experiment with [2-(13)C]-acetate revealed an unexpected incorporation pattern in the cyclopentenone functionality of hygrophorone B(12). Four single-labelled isotopomers, in particular [1-(13)C]-, [2-(13)C]-, [3-(13)C]-, and [4-(13)C]-hygrophorone B(12), were detected that showed only half enrichment in comparison to the respective labelled alkyl side chain carbons. This labelling pattern indicates the formation of a symmetrical intermediate during hygrophorone B(12) biosynthesis. Based on these observations, a biogenetic route via a 4-oxo fatty acid and a chrysotrione B homologue is discussed.

  2. Genome-Wide Analysis Reveals a Major Role in Cell Fate Maintenance and an Unexpected Role in Endoreduplication for the Drosophila FoxA Gene Fork Head

    PubMed Central

    Maruyama, Rika; Grevengoed, Elizabeth; Stempniewicz, Peter; Andrew, Deborah J.

    2011-01-01

    Transcription factors drive organogenesis, from the initiation of cell fate decisions to the maintenance and implementation of these decisions. The Drosophila embryonic salivary gland provides an excellent platform for unraveling the underlying transcriptional networks of organ development because Drosophila is relatively unencumbered by significant genetic redundancy. The highly conserved FoxA family transcription factors are essential for various aspects of organogenesis in all animals that have been studied. Here, we explore the role of the single Drosophila FoxA protein Fork head (Fkh) in salivary gland organogenesis using two genome-wide strategies. A large-scale in situ hybridization analysis reveals a major role for Fkh in maintaining the salivary gland fate decision and controlling salivary gland physiological activity, in addition to its previously known roles in morphogenesis and survival. The majority of salivary gland genes (59%) are affected by fkh loss, mainly at later stages of salivary gland development. We show that global expression of Fkh cannot drive ectopic salivary gland formation. Thus, unlike the worm FoxA protein PHA-4, Fkh does not function to specify cell fate. In addition, Fkh only indirectly regulates many salivary gland genes, which is also distinct from the role of PHA-4 in organogenesis. Our microarray analyses reveal unexpected roles for Fkh in blocking terminal differentiation and in endoreduplication in the salivary gland and in other Fkh-expressing embryonic tissues. Overall, this study demonstrates an important role for Fkh in determining how an organ preserves its identity throughout development and provides an alternative paradigm for how FoxA proteins function in organogenesis. PMID:21698206

  3. Transcriptomic Analysis of Autistic Brain Reveals Convergent Molecular Pathology

    PubMed Central

    Voineagu, Irina; Wang, Xinchen; Johnston, Patrick; Lowe, Jennifer K.; Tian, Yuan; Horvath, Steve; Mill, Jonathan; Cantor, Rita; Blencowe, Benjamin J.; Geschwind, Daniel H.

    2011-01-01

    Autism spectrum disorder (ASD) is a common, highly heritable neuro-developmental condition characterized by marked genetic heterogeneity1–3. Thus, a fundamental question is whether autism represents an etiologically heterogeneous disorder in which the myriad genetic or environmental risk factors perturb common underlying molecular pathways in the brain4. Here, we demonstrate consistent differences in transcriptome organization between autistic and normal brain by gene co-expression network analysis. Remarkably, regional patterns of gene expression that typically distinguish frontal and temporal cortex are significantly attenuated in the ASD brain, suggesting abnormalities in cortical patterning. We further identify discrete modules of co-expressed genes associated with autism: a neuronal module enriched for known autism susceptibility genes, including the neuronal specific splicing factor A2BP1/FOX1, and a module enriched for immune genes and glial markers. Using high-throughput RNA-sequencing we demonstrate dysregulated splicing of A2BP1-dependent alternative exons in ASD brain. Moreover, using a published autism GWAS dataset, we show that the neuronal module is enriched for genetically associated variants, providing independent support for the causal involvement of these genes in autism. In contrast, the immune-glial module showed no enrichment for autism GWAS signals, indicating a non-genetic etiology for this process. Collectively, our results provide strong evidence for convergent molecular abnormalities in ASD, and implicate transcriptional and splicing dysregulation as underlying mechanisms of neuronal dysfunction in this disorder. PMID:21614001

  4. Study Reveals Brain Biology behind Self-Control

    ERIC Educational Resources Information Center

    Sparks, Sarah D.

    2011-01-01

    A new neuroscience twist on a classic psychology study offers some clues to what makes one student able to buckle down for hours of homework before a test while his classmates party. The study published in the September 2011 edition of "Proceedings of the National Academy of Science," suggests environmental cues may "hijack" the brain's mechanisms…

  5. The Bilingual Brain as Revealed by Functional Neuroimaging.

    ERIC Educational Resources Information Center

    Abutalebi, Jubin; Cappa, Stefano F.; Perani, Daniela

    2001-01-01

    Functional neuroimaging of bilinguals and monolinguals used in conjunction with experimental cognitive tasks has been successful in establishing functional specialization as a principle of brain organization in humans. Consistent results show that attained proficiency and possibly language exposure are more important than age of acquisition as a…

  6. What Brain Sciences Reveal about Integrating Theory and Practice

    ERIC Educational Resources Information Center

    Patton, Michael Quinn

    2014-01-01

    Theory and practice are integrated in the human brain. Situation recognition and response are key to this integration. Scholars of decision making and expertise have found that people with great expertise are more adept at situational recognition and intentional about their decision-making processes. Several interdisciplinary fields of inquiry…

  7. Functional analysis of the TFIID-specific yeast TAF4 (yTAF(II)48) reveals an unexpected organization of its histone-fold domain.

    PubMed

    Thuault, Sylvie; Gangloff, Yann-Gaël; Kirchner, Jay; Sanders, Steven; Werten, Sebastiaan; Romier, Christophe; Weil, P Anthony; Davidson, Irwin

    2002-11-22

    Yeast TFIID comprises the TATA binding protein and 14 TBP-associated factors (TAF(II)s), nine of which contain histone-fold domains (HFDs). The C-terminal region of the TFIID-specific yTAF4 (yTAF(II)48) containing the HFD shares strong sequence similarity with Drosophila (d)TAF4 (dTAF(II)110) and human TAF4 (hTAF(II)135). A structure/function analysis of yTAF4 demonstrates that the HFD, a short conserved C-terminal domain (CCTD), and the region separating them are all required for yTAF4 function. Temperature-sensitive mutations in the yTAF4 HFD alpha2 helix or the CCTD can be suppressed upon overexpression of yTAF12 (yTAF(II)68). Moreover, coexpression in Escherichia coli indicates direct yTAF4-yTAF12 heterodimerization optimally requires both the yTAF4 HFD and CCTD. The x-ray crystal structure of the orthologous hTAF4-hTAF12 histone-like heterodimer indicates that the alpha3 region within the predicted TAF4 HFD is unstructured and does not correspond to the bona fide alpha3 helix. Our functional and biochemical analysis of yTAF4, rather provides strong evidence that the HFD alpha3 helix of the TAF4 family lies within the CCTD. These results reveal an unexpected and novel HFD organization in which the alpha3 helix is separated from the alpha2 helix by an extended loop containing a conserved functional domain. PMID:12237303

  8. Non-traumatic subdural hematoma secondary to septic brain embolism: A rare cause of unexpected death in a drug addict suffering from undiagnosed bacterial endocarditis.

    PubMed

    Geisenberger, D; Huppertz, L M; Büchsel, M; Kramer, L; Pollak, S; Grosse Perdekamp, M

    2015-12-01

    Acute subdural hematomas are mostly due to blunt traumatization of the head. In rare instances, subdural bleeding occurs without evidence of a previous trauma following spontaneous hemorrhage, e.g. from a ruptured aneurysm or an intracerebral hematoma perforating the brain surface and the arachnoid. The paper presents the morphological, microbiological and toxicological findings in a 38-year-old drug addict who was found by his partner in a dazed state. When brought to a hospital, he underwent trepanation to empty a right-sided subdural hematoma, but he died already 4h after admission. Autopsy revealed previously undiagnosed infective endocarditis of the aortic valve as well as multiple infarctions of brain, spleen and kidneys obviously caused by septic emboli. The subdural hematoma originated from a subcortical brain hemorrhage which had perforated into the subdural space. Microbiological investigation of the polypous vegetations adhering to the aortic valve revealed colonization by Streptococcus mitis and Klebsiella oxytoca. According to the toxicological analysis, no psychotropic substances had contributed to the lethal outcome. The case reported underlines that all deaths of drug addicts should be subjected to complete forensic autopsy, as apart from intoxications also natural and traumatic causes of death have to be taken into consideration.

  9. Non-traumatic subdural hematoma secondary to septic brain embolism: A rare cause of unexpected death in a drug addict suffering from undiagnosed bacterial endocarditis.

    PubMed

    Geisenberger, D; Huppertz, L M; Büchsel, M; Kramer, L; Pollak, S; Grosse Perdekamp, M

    2015-12-01

    Acute subdural hematomas are mostly due to blunt traumatization of the head. In rare instances, subdural bleeding occurs without evidence of a previous trauma following spontaneous hemorrhage, e.g. from a ruptured aneurysm or an intracerebral hematoma perforating the brain surface and the arachnoid. The paper presents the morphological, microbiological and toxicological findings in a 38-year-old drug addict who was found by his partner in a dazed state. When brought to a hospital, he underwent trepanation to empty a right-sided subdural hematoma, but he died already 4h after admission. Autopsy revealed previously undiagnosed infective endocarditis of the aortic valve as well as multiple infarctions of brain, spleen and kidneys obviously caused by septic emboli. The subdural hematoma originated from a subcortical brain hemorrhage which had perforated into the subdural space. Microbiological investigation of the polypous vegetations adhering to the aortic valve revealed colonization by Streptococcus mitis and Klebsiella oxytoca. According to the toxicological analysis, no psychotropic substances had contributed to the lethal outcome. The case reported underlines that all deaths of drug addicts should be subjected to complete forensic autopsy, as apart from intoxications also natural and traumatic causes of death have to be taken into consideration. PMID:26296471

  10. Brain potentials reveal unconscious translation during foreign-language comprehension

    PubMed Central

    Thierry, Guillaume; Wu, Yan Jing

    2007-01-01

    Whether the native language of bilingual individuals is active during second-language comprehension is the subject of lively debate. Studies of bilingualism have often used a mix of first- and second-language words, thereby creating an artificial “dual-language” context. Here, using event-related brain potentials, we demonstrate implicit access to the first language when bilinguals read words exclusively in their second language. Chinese–English bilinguals were required to decide whether English words presented in pairs were related in meaning or not; they were unaware of the fact that half of the words concealed a character repetition when translated into Chinese. Whereas the hidden factor failed to affect behavioral performance, it significantly modulated brain potentials in the expected direction, establishing that English words were automatically and unconsciously translated into Chinese. Critically, the same modulation was found in Chinese monolinguals reading the same words in Chinese, i.e., when Chinese character repetition was evident. Finally, we replicated this pattern of results in the auditory modality by using a listening comprehension task. These findings demonstrate that native-language activation is an unconscious correlate of second-language comprehension. PMID:17630288

  11. Unexpected tolerance of glycosylation by UDP-GalNAc:polypeptide alpha-N-acetylgalactosaminyltransferase revealed by electron capture dissociation mass spectrometry: carbohydrate as potential protective groups.

    PubMed

    Yoshimura, Yayoi; Matsushita, Takahiko; Fujitani, Naoki; Takegawa, Yasuhiro; Fujihira, Haruhiko; Naruchi, Kentarou; Gao, Xiao-Dong; Manri, Naomi; Sakamoto, Takeshi; Kato, Kentaro; Hinou, Hiroshi; Nishimura, Shin-Ichiro

    2010-07-20

    UDP-GalNAc:polypeptide alpha-N-acetylgalactosaminyltransferases (ppGalNAcTs, EC 2.4.1.41), a family of key enzymes that initiate posttranslational modification with O-glycans in mucin synthesis by introduction of alpha-GalNAc residues, are structurally composed of a catalytic domain and a lectin domain. It has been known that multiple Ser/Thr residues are assigned in common mucin glycoproteins as potential O-glycosylation sites and more than 20 distinct isoforms of this enzyme family contribute to produce densely O-glycosylated mucin glycoproteins. However, it seems that the functional role of the lectin domain of ppGalNAcTs remains unclear. We considered that electron capture dissociation mass spectrometry (ECD-MS), a promising method for highly selective fragmentation at peptide linkages of glycopeptides to generate unique c and z series of ions, should allow for precise structural characterization to uncover the mechanism in O-glycosylation of mucin peptides by ppGalNAcTs. In the present study, it was demonstrated that a system composed of an electrospray source, a linear RFQ ion trap that isolates precursor ions, the ECD device, and a TOF mass spectrometer is a nice tool to identify the preferential O-glycosylation sites without any decomposition of the carbohydrate moiety. It should be noted that electrons used for ECD are accelerated within a range from 1.75 to 9.75 eV depending on the structures of glycopeptides of interest. We revealed for the first time that additional installation of a alpha-GalNAc residue at potential glycosylation sites by ppGalNAcT2 proceeds smoothly in various unnatural glycopeptides having alpha-Man, alpha-Fuc, and beta-Gal residues as well as alpha-GalNAc residues. The results may suggest that ppGalNAcT2 did not differentiate totally presubstituted sugar residues in terms of configuration of functional groups, d-, l-configuration, and even alpha-, beta-stereochemistry at an anomeric carbon atom when relatively short synthetic

  12. Hidden Stages of Cognition Revealed in Patterns of Brain Activation.

    PubMed

    Anderson, John R; Pyke, Aryn A; Fincham, Jon M

    2016-09-01

    To advance cognitive theory, researchers must be able to parse the performance of a task into its significant mental stages. In this article, we describe a new method that uses functional MRI brain activation to identify when participants are engaged in different cognitive stages on individual trials. The method combines multivoxel pattern analysis to identify cognitive stages and hidden semi-Markov models to identify their durations. This method, applied to a problem-solving task, identified four distinct stages: encoding, planning, solving, and responding. We examined whether these stages corresponded to their ascribed functions by testing whether they are affected by appropriate factors. Planning-stage duration increased as the method for solving the problem became less obvious, whereas solving-stage duration increased as the number of calculations to produce the answer increased. Responding-stage duration increased with the difficulty of the motor actions required to produce the answer. PMID:27440808

  13. Sleep Deprivation Reveals Altered Brain Perfusion Patterns in Somnambulism

    PubMed Central

    Dang-Vu, Thien Thanh; Zadra, Antonio; Labelle, Marc-Antoine; Petit, Dominique; Soucy, Jean-Paul; Montplaisir, Jacques

    2015-01-01

    Background Despite its high prevalence, relatively little is known about the pathophysiology of somnambulism. Increasing evidence indicates that somnambulism is associated with functional abnormalities during wakefulness and that sleep deprivation constitutes an important drive that facilitates sleepwalking in predisposed patients. Here, we studied the neural mechanisms associated with somnambulism using Single Photon Emission Computed Tomography (SPECT) with 99mTc-Ethylene Cysteinate Dimer (ECD), during wakefulness and after sleep deprivation. Methods Ten adult sleepwalkers and twelve controls with normal sleep were scanned using 99mTc-ECD SPECT in morning wakefulness after a full night of sleep. Eight of the sleepwalkers and nine of the controls were also scanned during wakefulness after a night of total sleep deprivation. Between-group comparisons of regional cerebral blood flow (rCBF) were performed to characterize brain activity patterns during wakefulness in sleepwalkers. Results During wakefulness following a night of total sleep deprivation, rCBF was decreased bilaterally in the inferior temporal gyrus in sleepwalkers compared to controls. Conclusions Functional neural abnormalities can be observed during wakefulness in somnambulism, particularly after sleep deprivation and in the inferior temporal cortex. Sleep deprivation thus not only facilitates the occurrence of sleepwalking episodes, but also uncovers patterns of neural dysfunction that characterize sleepwalkers during wakefulness. PMID:26241047

  14. [Information processing in the human brain revealed by eyeblink].

    PubMed

    Nakano, Tamami

    2014-01-01

    People spontaneously generate an eyeblink every few seconds. It is generally accepted that eyeblinks are necessary for ocular lubrication, but spontaneous eyeblinks actually occur several times more frequently than necessary for lubrication. Thus, the functional role of most spontaneous eyeblinks has remained unclear. We found that peoples blinked in synchrony while viewing the same video stories. This blink synchronization specifically occured at the implicit breakpoints of the video stories. Moreover, in face-to-face communication, the listeners blinked with a delay of 0.25-0.5 s after the speaker blinked at the end and during pauses in speech. In contrast, the individuals with autism spectrum disorders, which are characterized by impaired social communication, did not show any eyeblink synchronization with the speaker. These facts demonstrate that spontaneous eyeblink is involved in the contextual segmentation of information, and that eyeblinks have a social function to share the contextual segmentation with others. Futhermore, our neuroimaging study revealed that, while viewing videos, cortical activity momentarily decreases in the dorsal attention network after blink onset but increases in the default-mode network. These results suggest that the spontaneous eyeblink is involved in the disengagement of attention at an implicit contextual breakpoint by controlling the balance between the two competing networks. PMID:24371126

  15. Educational games for brain health: revealing their unexplored potential through a neurocognitive approach

    PubMed Central

    Fissler, Patrick; Kolassa, Iris-Tatjana; Schrader, Claudia

    2015-01-01

    Educational games link the motivational nature of games with learning of knowledge and skills. Here, we go beyond effects on these learning outcomes. We review two lines of evidence which indicate the currently unexplored potential of educational games to promote brain health: First, gaming with specific neurocognitive demands (e.g., executive control), and second, educational learning experiences (e.g., studying foreign languages) improve brain health markers. These markers include cognitive ability, brain function, and brain structure. As educational games allow the combination of specific neurocognitive demands with educational learning experiences, they seem to be optimally suited for promoting brain health. We propose a neurocognitive approach to reveal this unexplored potential of educational games in future research. PMID:26257697

  16. Educational games for brain health: revealing their unexplored potential through a neurocognitive approach.

    PubMed

    Fissler, Patrick; Kolassa, Iris-Tatjana; Schrader, Claudia

    2015-01-01

    Educational games link the motivational nature of games with learning of knowledge and skills. Here, we go beyond effects on these learning outcomes. We review two lines of evidence which indicate the currently unexplored potential of educational games to promote brain health: First, gaming with specific neurocognitive demands (e.g., executive control), and second, educational learning experiences (e.g., studying foreign languages) improve brain health markers. These markers include cognitive ability, brain function, and brain structure. As educational games allow the combination of specific neurocognitive demands with educational learning experiences, they seem to be optimally suited for promoting brain health. We propose a neurocognitive approach to reveal this unexplored potential of educational games in future research. PMID:26257697

  17. Educational games for brain health: revealing their unexplored potential through a neurocognitive approach.

    PubMed

    Fissler, Patrick; Kolassa, Iris-Tatjana; Schrader, Claudia

    2015-01-01

    Educational games link the motivational nature of games with learning of knowledge and skills. Here, we go beyond effects on these learning outcomes. We review two lines of evidence which indicate the currently unexplored potential of educational games to promote brain health: First, gaming with specific neurocognitive demands (e.g., executive control), and second, educational learning experiences (e.g., studying foreign languages) improve brain health markers. These markers include cognitive ability, brain function, and brain structure. As educational games allow the combination of specific neurocognitive demands with educational learning experiences, they seem to be optimally suited for promoting brain health. We propose a neurocognitive approach to reveal this unexplored potential of educational games in future research.

  18. Multivariate pattern analysis reveals subtle brain anomalies relevant to the cognitive phenotype in neurofibromatosis type 1.

    PubMed

    Duarte, João V; Ribeiro, Maria J; Violante, Inês R; Cunha, Gil; Silva, Eduardo; Castelo-Branco, Miguel

    2014-01-01

    Neurofibromatosis Type 1 (NF1) is a common genetic condition associated with cognitive dysfunction. However, the pathophysiology of the NF1 cognitive deficits is not well understood. Abnormal brain structure, including increased total brain volume, white matter (WM) and grey matter (GM) abnormalities have been reported in the NF1 brain. These previous studies employed univariate model-driven methods preventing detection of subtle and spatially distributed differences in brain anatomy. Multivariate pattern analysis allows the combination of information from multiple spatial locations yielding a discriminative power beyond that of single voxels. Here we investigated for the first time subtle anomalies in the NF1 brain, using a multivariate data-driven classification approach. We used support vector machines (SVM) to classify whole-brain GM and WM segments of structural T1 -weighted MRI scans from 39 participants with NF1 and 60 non-affected individuals, divided in children/adolescents and adults groups. We also employed voxel-based morphometry (VBM) as a univariate gold standard to study brain structural differences. SVM classifiers correctly classified 94% of cases (sensitivity 92%; specificity 96%) revealing the existence of brain structural anomalies that discriminate NF1 individuals from controls. Accordingly, VBM analysis revealed structural differences in agreement with the SVM weight maps representing the most relevant brain regions for group discrimination. These included the hippocampus, basal ganglia, thalamus, and visual cortex. This multivariate data-driven analysis thus identified subtle anomalies in brain structure in the absence of visible pathology. Our results provide further insight into the neuroanatomical correlates of known features of the cognitive phenotype of NF1.

  19. Hemispheric Asymmetry of Human Brain Anatomical Network Revealed by Diffusion Tensor Tractography

    PubMed Central

    Shu, Ni; Liu, Yaou; Duan, Yunyun; Li, Kuncheng

    2015-01-01

    The topological architecture of the cerebral anatomical network reflects the structural organization of the human brain. Recently, topological measures based on graph theory have provided new approaches for quantifying large-scale anatomical networks. However, few studies have investigated the hemispheric asymmetries of the human brain from the perspective of the network model, and little is known about the asymmetries of the connection patterns of brain regions, which may reflect the functional integration and interaction between different regions. Here, we utilized diffusion tensor imaging to construct binary anatomical networks for 72 right-handed healthy adult subjects. We established the existence of structural connections between any pair of the 90 cortical and subcortical regions using deterministic tractography. To investigate the hemispheric asymmetries of the brain, statistical analyses were performed to reveal the brain regions with significant differences between bilateral topological properties, such as degree of connectivity, characteristic path length, and betweenness centrality. Furthermore, local structural connections were also investigated to examine the local asymmetries of some specific white matter tracts. From the perspective of both the global and local connection patterns, we identified the brain regions with hemispheric asymmetries. Combined with the previous studies, we suggested that the topological asymmetries in the anatomical network may reflect the functional lateralization of the human brain. PMID:26539535

  20. Hemispheric Asymmetry of Human Brain Anatomical Network Revealed by Diffusion Tensor Tractography.

    PubMed

    Shu, Ni; Liu, Yaou; Duan, Yunyun; Li, Kuncheng

    2015-01-01

    The topological architecture of the cerebral anatomical network reflects the structural organization of the human brain. Recently, topological measures based on graph theory have provided new approaches for quantifying large-scale anatomical networks. However, few studies have investigated the hemispheric asymmetries of the human brain from the perspective of the network model, and little is known about the asymmetries of the connection patterns of brain regions, which may reflect the functional integration and interaction between different regions. Here, we utilized diffusion tensor imaging to construct binary anatomical networks for 72 right-handed healthy adult subjects. We established the existence of structural connections between any pair of the 90 cortical and subcortical regions using deterministic tractography. To investigate the hemispheric asymmetries of the brain, statistical analyses were performed to reveal the brain regions with significant differences between bilateral topological properties, such as degree of connectivity, characteristic path length, and betweenness centrality. Furthermore, local structural connections were also investigated to examine the local asymmetries of some specific white matter tracts. From the perspective of both the global and local connection patterns, we identified the brain regions with hemispheric asymmetries. Combined with the previous studies, we suggested that the topological asymmetries in the anatomical network may reflect the functional lateralization of the human brain.

  1. Impaired inter-hemispheric integration in bipolar disorder revealed using brain network analyses

    PubMed Central

    Leow, Alex; Ajilore, Olusola; Zhan, Liang; Arienzo, Donatello; GadElkarim, Johnson; Zhang, Aifeng; Moody, Teena; Van Horn, John; Feusner, Jamie; Kumar, Anand; Thompson, Paul; Altshuler, Lori

    2014-01-01

    Background This represents the first graph theory based brain network analysis study in bipolar disorder, a chronic and disabling psychiatric disorder characterized by severe mood swings. Many imaging studies have investigated white matter in bipolar disorder with results suggesting abnormal white matter structural integrity, particularly in the fronto-limbic and callosal systems. However, many inconsistencies remain in the literature, and no study to-date has conducted brain network analyses using a graph-theoretic approach. Methods We acquired 64-direction diffusion-weighted MRI on 25 euthymic bipolar I disorder subjects and 24 gender and age equivalent healthy subjects. White matter integrity measures including fractional anisotropy and mean diffusivity were compared in the whole brain. Additionally, structural connectivity matrices based on whole brain deterministic tractography were constructed followed by the computation of both global and local brain network measures. We also designed novel metrics to further probe inter-hemispheric integration. Results Network analyses revealed that the bipolar brain networks exhibited significantly longer characteristic path length, lower clustering coefficient, and lower global efficiency relative to those of controls. Further analyses revealed impaired inter-hemispheric but relatively preserved intra-hemispheric integration. These findings were supported by whole brain white matter analyses that revealed significantly lower integrity in the corpus callosum in bipolar subjects. There were also abnormalities in nodal network measures in structures within the limbic system, especially the left hippocampus, the left lateral orbito-frontal cortex, and the bilateral isthmus cingulate. Conclusions These results suggest abnormalities in structural network organization in bipolar disorder, particularly in inter-hemispheric integration and within the limbic system. PMID:23122540

  2. Characterization of traumatic brain injury in human brains reveals distinct cellular and molecular changes in contusion and pericontusion.

    PubMed

    Harish, Gangadharappa; Mahadevan, Anita; Pruthi, Nupur; Sreenivasamurthy, Sreelakshmi K; Puttamallesh, Vinuth N; Keshava Prasad, Thottethodi Subrahmanya; Shankar, Susarla Krishna; Srinivas Bharath, Muchukunte Mukunda

    2015-07-01

    Traumatic brain injury (TBI) contributes to fatalities and neurological disabilities worldwide. While primary injury causes immediate damage, secondary events contribute to long-term neurological defects. Contusions (Ct) are primary injuries correlated with poor clinical prognosis, and can expand leading to delayed neurological deterioration. Pericontusion (PC) (penumbra), the region surrounding Ct, can also expand with edema, increased intracranial pressure, ischemia, and poor clinical outcome. Analysis of Ct and PC can therefore assist in understanding the pathobiology of TBI and its management. This study on human TBI brains noted extensive neuronal, astroglial and inflammatory changes, alterations in mitochondrial, synaptic and oxidative markers, and associated proteomic profile, with distinct differences in Ct and PC. While Ct displayed petechial hemorrhages, thrombosis, inflammation, neuronal pyknosis, and astrogliosis, PC revealed edema, vacuolation of neuropil, axonal loss, and dystrophic changes. Proteomic analysis demonstrated altered immune response, synaptic, and mitochondrial dysfunction, among others, in Ct, while PC displayed altered regulation of neurogenesis and cytoskeletal architecture, among others. TBI brains displayed oxidative damage, glutathione depletion, mitochondrial dysfunction, and loss of synaptic proteins, with these changes being more profound in Ct. We suggest that analysis of markers specific to Ct and PC may be valuable in the evaluation of TBI pathobiology and therapeutics. We have characterized the primary injury in human traumatic brain injury (TBI). Contusions (Ct) - the injury core displayed hemorrhages, inflammation, and astrogliosis, while the surrounding pericontusion (PC) revealed edema, vacuolation, microglial activation, axonal loss, and dystrophy. Proteomic analysis demonstrated altered immune response, synaptic and mitochondrial dysfunction in Ct, and altered regulation of neurogenesis and cytoskeletal architecture in

  3. Analysis of spatial-temporal gene expression patterns reveals dynamics and regionalization in developing mouse brain

    PubMed Central

    Chou, Shen-Ju; Wang, Chindi; Sintupisut, Nardnisa; Niou, Zhen-Xian; Lin, Chih-Hsu; Li, Ker-Chau; Yeang, Chen-Hsiang

    2016-01-01

    Allen Brain Atlas (ABA) provides a valuable resource of spatial/temporal gene expressions in mammalian brains. Despite rich information extracted from this database, current analyses suffer from several limitations. First, most studies are either gene-centric or region-centric, thus are inadequate to capture the superposition of multiple spatial-temporal patterns. Second, standard tools of expression analysis such as matrix factorization can capture those patterns but do not explicitly incorporate spatial dependency. To overcome those limitations, we proposed a computational method to detect recurrent patterns in the spatial-temporal gene expression data of developing mouse brains. We demonstrated that regional distinction in brain development could be revealed by localized gene expression patterns. The patterns expressed in the forebrain, medullary and pontomedullary, and basal ganglia are enriched with genes involved in forebrain development, locomotory behavior, and dopamine metabolism respectively. In addition, the timing of global gene expression patterns reflects the general trends of molecular events in mouse brain development. Furthermore, we validated functional implications of the inferred patterns by showing genes sharing similar spatial-temporal expression patterns with Lhx2 exhibited differential expression in the embryonic forebrains of Lhx2 mutant mice. These analysis outcomes confirm the utility of recurrent expression patterns in studying brain development. PMID:26786896

  4. Screening of random peptide library of hemagglutinin from pandemic 2009 A(H1N1) influenza virus reveals unexpected antigenically important regions.

    PubMed

    Xu, Wanghui; Han, Lu; Lin, Zhanglin

    2011-01-01

    The antigenic structure of the membrane protein hemagglutinin (HA) from the 2009 A(H1N1) influenza virus was dissected with a high-throughput screening method using complex antisera. The approach involves generating yeast cell libraries displaying a pool of random peptides of controllable lengths on the cell surface, followed by one round of fluorescence-activated cell sorting (FACS) against antisera from mouse, goat and human, respectively. The amino acid residue frequency appearing in the antigenic peptides at both the primary sequence and structural level was determined and used to identify "hot spots" or antigenically important regions. Unexpectedly, different antigenic structures were seen for different antisera. Moreover, five antigenic regions were identified, of which all but one are located in the conserved HA stem region that is responsible for membrane fusion. Our findings are corroborated by several recent studies on cross-neutralizing H1 subtype antibodies that recognize the HA stem region. The antigenic peptides identified may provide clues for creating peptide vaccines with better accessibility to memory B cells and better induction of cross-neutralizing antibodies than the whole HA protein. The scheme used in this study enables a direct mapping of the antigenic regions of viral proteins recognized by antisera, and may be useful for dissecting the antigenic structures of other viral proteins. PMID:21437206

  5. Brain science and illness beliefs: an unexpected explanation of the healing power of therapeutic conversations and the family interventions that matter.

    PubMed

    Wright, Lorraine M

    2015-05-01

    Paradigm families and paradigm practice moments have shown me that therapeutic conversations between nurses and families can profoundly and positively change illness beliefs in family members and nurses and contribute to healing from serious illness. The integration of brain science into nursing practice offers further understanding of the importance of illness beliefs and the role they may play in helping individual and family healing. Brain science offers explanations that connect how certain family nursing interventions that soften suffering and challenge constraining illness beliefs may result in changes in brain structure and functioning. New illness beliefs may result in new neural pathways in the brain, and therefore, possibilities for a new way of being in relationship with illness and in relationship with others can also develop. Newly acquired practice skills and interventions that have emerged from an understanding of brain science plus the reemphasis of other interventions utilized in the Illness Beliefs Model are offered to enhance our care of families suffering with illness.

  6. Evolving the stimulus to fit the brain: a genetic algorithm reveals the brain's feature priorities in visual search.

    PubMed

    Van der Burg, Erik; Cass, John; Theeuwes, Jan; Alais, David

    2015-02-06

    How does the brain find objects in cluttered visual environments? For decades researchers have employed the classic visual search paradigm to answer this question using factorial designs. Although such approaches have yielded important information, they represent only a tiny fraction of the possible parametric space. Here we use a novel approach, by using a genetic algorithm (GA) to discover the way the brain solves visual search in complex environments, free from experimenter bias. Participants searched a series of complex displays, and those supporting fastest search were selected to reproduce (survival of the fittest). Their display properties (genes) were crossed and combined to create a new generation of "evolved" displays. Displays evolved quickly over generations towards a stable, efficiently searched array. Color properties evolved first, followed by orientation. The evolved displays also contained spatial patterns suggesting a coarse-to-fine search strategy. We argue that this behavioral performance-driven GA reveals the way the brain selects information during visual search in complex environments. We anticipate that our approach can be adapted to a variety of sensory and cognitive questions that have proven too intractable for factorial designs.

  7. Circuit-wide Transcriptional Profiling Reveals Brain Region-Specific Gene Networks Regulating Depression Susceptibility.

    PubMed

    Bagot, Rosemary C; Cates, Hannah M; Purushothaman, Immanuel; Lorsch, Zachary S; Walker, Deena M; Wang, Junshi; Huang, Xiaojie; Schlüter, Oliver M; Maze, Ian; Peña, Catherine J; Heller, Elizabeth A; Issler, Orna; Wang, Minghui; Song, Won-Min; Stein, Jason L; Liu, Xiaochuan; Doyle, Marie A; Scobie, Kimberly N; Sun, Hao Sheng; Neve, Rachael L; Geschwind, Daniel; Dong, Yan; Shen, Li; Zhang, Bin; Nestler, Eric J

    2016-06-01

    Depression is a complex, heterogeneous disorder and a leading contributor to the global burden of disease. Most previous research has focused on individual brain regions and genes contributing to depression. However, emerging evidence in humans and animal models suggests that dysregulated circuit function and gene expression across multiple brain regions drive depressive phenotypes. Here, we performed RNA sequencing on four brain regions from control animals and those susceptible or resilient to chronic social defeat stress at multiple time points. We employed an integrative network biology approach to identify transcriptional networks and key driver genes that regulate susceptibility to depressive-like symptoms. Further, we validated in vivo several key drivers and their associated transcriptional networks that regulate depression susceptibility and confirmed their functional significance at the levels of gene transcription, synaptic regulation, and behavior. Our study reveals novel transcriptional networks that control stress susceptibility and offers fundamentally new leads for antidepressant drug discovery.

  8. Neuronal subtypes and diversity revealed by single-nucleus RNA sequencing of the human brain

    PubMed Central

    Lake, Blue B.; Ai, Rizi; Kaeser, Gwendolyn E.; Salathia, Neeraj S.; Yung, Yun C.; Liu, Rui; Wildberg, Andre; Gao, Derek; Fung, Ho-Lim; Chen, Song; Vijayaraghavan, Raakhee; Wong, Julian; Chen, Allison; Sheng, Xiaoyan; Kaper, Fiona; Shen, Richard; Ronaghi, Mostafa; Fan, Jian-Bing; Wang, Wei; Chun, Jerold; Zhang, Kun

    2016-01-01

    The human brain has enormously complex cellular diversity and connectivities fundamental to our neural functions, yet difficulties in interrogating individual neurons has impeded understanding of the underlying transcriptional landscape. We developed a scalable approach to sequence and quantify RNA molecules in isolated neuronal nuclei from post-mortem brain, generating 3,227 sets of single neuron data from six distinct regions of the cerebral cortex. Using an iterative clustering and classification approach, we identified 16 neuronal subtypes that were further annotated on the basis of known markers and cortical cytoarchitecture. These data demonstrate a robust and scalable method for identifying and categorizing single nuclear transcriptomes, revealing shared genes sufficient to distinguish novel and orthologous neuronal subtypes as well as regional identity within the human brain. PMID:27339989

  9. Experience and the ever-changing brain: What the transcriptome can reveal

    PubMed Central

    Rubin, Todd G.; Gray, Jason D.; McEwen, Bruce S.

    2015-01-01

    The brain is an ever-changing organ that encodes memories and directs behavior. Neuroanatomical studies have revealed structural plasticity of neural architecture, and advances in gene expression technology and epigenetics have demonstrated new mechanisms underlying the brain’s dynamic nature. Stressful experiences challenge the plasticity of the brain, and prolonged exposure to environmental stress redefines the normative transcriptional profile of both neurons and glia, and can lead to the onset of mental illness. A more thorough understanding of normal and abnormal gene expression is needed to define the diseased brain and improve current treatments for psychiatric disorders. The efforts to describe gene expression networks have been bolstered by microarray and RNA-sequencing technologies. The heterogeneity of neural cell populations and their unique microenvironments, coupled with broad ranging interconnectivity, makes resolving this complexity exceedingly challenging and requires the combined efforts of single cell and systems level expression profiling to identify targets for therapeutic intervention. PMID:25213333

  10. Neuronal subtypes and diversity revealed by single-nucleus RNA sequencing of the human brain.

    PubMed

    Lake, Blue B; Ai, Rizi; Kaeser, Gwendolyn E; Salathia, Neeraj S; Yung, Yun C; Liu, Rui; Wildberg, Andre; Gao, Derek; Fung, Ho-Lim; Chen, Song; Vijayaraghavan, Raakhee; Wong, Julian; Chen, Allison; Sheng, Xiaoyan; Kaper, Fiona; Shen, Richard; Ronaghi, Mostafa; Fan, Jian-Bing; Wang, Wei; Chun, Jerold; Zhang, Kun

    2016-06-24

    The human brain has enormously complex cellular diversity and connectivities fundamental to our neural functions, yet difficulties in interrogating individual neurons has impeded understanding of the underlying transcriptional landscape. We developed a scalable approach to sequence and quantify RNA molecules in isolated neuronal nuclei from a postmortem brain, generating 3227 sets of single-neuron data from six distinct regions of the cerebral cortex. Using an iterative clustering and classification approach, we identified 16 neuronal subtypes that were further annotated on the basis of known markers and cortical cytoarchitecture. These data demonstrate a robust and scalable method for identifying and categorizing single nuclear transcriptomes, revealing shared genes sufficient to distinguish previously unknown and orthologous neuronal subtypes as well as regional identity and transcriptomic heterogeneity within the human brain. PMID:27339989

  11. Circuit-wide Transcriptional Profiling Reveals Brain Region-Specific Gene Networks Regulating Depression Susceptibility.

    PubMed

    Bagot, Rosemary C; Cates, Hannah M; Purushothaman, Immanuel; Lorsch, Zachary S; Walker, Deena M; Wang, Junshi; Huang, Xiaojie; Schlüter, Oliver M; Maze, Ian; Peña, Catherine J; Heller, Elizabeth A; Issler, Orna; Wang, Minghui; Song, Won-Min; Stein, Jason L; Liu, Xiaochuan; Doyle, Marie A; Scobie, Kimberly N; Sun, Hao Sheng; Neve, Rachael L; Geschwind, Daniel; Dong, Yan; Shen, Li; Zhang, Bin; Nestler, Eric J

    2016-06-01

    Depression is a complex, heterogeneous disorder and a leading contributor to the global burden of disease. Most previous research has focused on individual brain regions and genes contributing to depression. However, emerging evidence in humans and animal models suggests that dysregulated circuit function and gene expression across multiple brain regions drive depressive phenotypes. Here, we performed RNA sequencing on four brain regions from control animals and those susceptible or resilient to chronic social defeat stress at multiple time points. We employed an integrative network biology approach to identify transcriptional networks and key driver genes that regulate susceptibility to depressive-like symptoms. Further, we validated in vivo several key drivers and their associated transcriptional networks that regulate depression susceptibility and confirmed their functional significance at the levels of gene transcription, synaptic regulation, and behavior. Our study reveals novel transcriptional networks that control stress susceptibility and offers fundamentally new leads for antidepressant drug discovery. PMID:27181059

  12. Tensor-Based Morphometry Reveals Volumetric Deficits in Moderate=Severe Pediatric Traumatic Brain Injury

    PubMed Central

    Hua, Xue; Villalon-Reina, Julio; Moran, Lisa M.; Kernan, Claudia; Babikian, Talin; Mink, Richard; Babbitt, Christopher; Johnson, Jeffrey; Giza, Christopher C.; Thompson, Paul M.; Asarnow, Robert F.

    2016-01-01

    Abstract Traumatic brain injury (TBI) can cause widespread and prolonged brain degeneration. TBI can affect cognitive function and brain integrity for many years after injury, often with lasting effects in children, whose brains are still immature. Although TBI varies in how it affects different individuals, image analysis methods such as tensor-based morphometry (TBM) can reveal common areas of brain atrophy on magnetic resonance imaging (MRI), secondary effects of the initial injury, which will differ between subjects. Here we studied 36 pediatric moderate to severe TBI (msTBI) participants in the post-acute phase (1–6 months post-injury) and 18 msTBI participants who returned for their chronic assessment, along with well-matched controls at both time-points. Participants completed a battery of cognitive tests that we used to create a global cognitive performance score. Using TBM, we created three-dimensional (3D) maps of individual and group differences in regional brain volumes. At both the post-acute and chronic time-points, the greatest group differences were expansion of the lateral ventricles and reduction of the lingual gyrus in the TBI group. We found a number of smaller clusters of volume reduction in the cingulate gyrus, thalamus, and fusiform gyrus, and throughout the frontal, temporal, and parietal cortices. Additionally, we found extensive associations between our cognitive performance measure and regional brain volume. Our results indicate a pattern of atrophy still detectable 1-year post-injury, which may partially underlie the cognitive deficits frequently found in TBI. PMID:26393494

  13. Requirement for interleukin-1 to drive brain inflammation reveals tissue-specific mechanisms of innate immunity.

    PubMed

    Giles, James A; Greenhalgh, Andrew D; Davies, Claire L; Denes, Adam; Shaw, Tovah; Coutts, Graham; Rothwell, Nancy J; McColl, Barry W; Allan, Stuart M

    2015-02-01

    The immune system is implicated in a wide range of disorders affecting the brain and is, therefore, an attractive target for therapy. Interleukin-1 (IL-1) is a potent regulator of the innate immune system important for host defense but is also associated with injury and disease in the brain. Here, we show that IL-1 is a key mediator driving an innate immune response to inflammatory challenge in the mouse brain but is dispensable in extracerebral tissues including the lung and peritoneum. We also demonstrate that IL-1α is an important ligand contributing to the CNS dependence on IL-1 and that IL-1 derived from the CNS compartment (most likely microglia) is the major source driving this effect. These data reveal previously unknown tissue-specific requirements for IL-1 in driving innate immunity and suggest that IL-1-mediated inflammation in the brain could be selectively targeted without compromising systemic innate immune responses that are important for resistance to infection. This property could be exploited to mitigate injury- and disease-associated inflammation in the brain without increasing susceptibility to systemic infection, an important complication in several neurological disorders.

  14. Metabolic connectivity mapping reveals effective connectivity in the resting human brain.

    PubMed

    Riedl, Valentin; Utz, Lukas; Castrillón, Gabriel; Grimmer, Timo; Rauschecker, Josef P; Ploner, Markus; Friston, Karl J; Drzezga, Alexander; Sorg, Christian

    2016-01-12

    Directionality of signaling among brain regions provides essential information about human cognition and disease states. Assessing such effective connectivity (EC) across brain states using functional magnetic resonance imaging (fMRI) alone has proven difficult, however. We propose a novel measure of EC, termed metabolic connectivity mapping (MCM), that integrates undirected functional connectivity (FC) with local energy metabolism from fMRI and positron emission tomography (PET) data acquired simultaneously. This method is based on the concept that most energy required for neuronal communication is consumed postsynaptically, i.e., at the target neurons. We investigated MCM and possible changes in EC within the physiological range using "eyes open" versus "eyes closed" conditions in healthy subjects. Independent of condition, MCM reliably detected stable and bidirectional communication between early and higher visual regions. Moreover, we found stable top-down signaling from a frontoparietal network including frontal eye fields. In contrast, we found additional top-down signaling from all major clusters of the salience network to early visual cortex only in the eyes open condition. MCM revealed consistent bidirectional and unidirectional signaling across the entire cortex, along with prominent changes in network interactions across two simple brain states. We propose MCM as a novel approach for inferring EC from neuronal energy metabolism that is ideally suited to study signaling hierarchies in the brain and their defects in brain disorders.

  15. Whole-brain circuit dissection in free-moving animals reveals cell-specific mesocorticolimbic networks

    PubMed Central

    Michaelides, Michael; Anderson, Sarah Ann R.; Ananth, Mala; Smirnov, Denis; Thanos, Panayotis K.; Neumaier, John F.; Wang, Gene-Jack; Volkow, Nora D.; Hurd, Yasmin L.

    2013-01-01

    The ability to map the functional connectivity of discrete cell types in the intact mammalian brain during behavior is crucial for advancing our understanding of brain function in normal and disease states. We combined designer receptor exclusively activated by designer drug (DREADD) technology and behavioral imaging with μPET and [18F]fluorodeoxyglucose (FDG) to generate whole-brain metabolic maps of cell-specific functional circuits during the awake, freely moving state. We have termed this approach DREADD-assisted metabolic mapping (DREAMM) and documented its ability in rats to map whole-brain functional anatomy. We applied this strategy to evaluating changes in the brain associated with inhibition of prodynorphin-expressing (Pdyn-expressing) and of proenkephalin-expressing (Penk-expressing) medium spiny neurons (MSNs) of the nucleus accumbens shell (NAcSh), which have been implicated in neuropsychiatric disorders. DREAMM revealed discrete behavioral manifestations and concurrent engagement of distinct corticolimbic networks associated with dysregulation of Pdyn and Penk in MSNs of the NAcSh. Furthermore, distinct neuronal networks were recruited in awake versus anesthetized conditions. These data demonstrate that DREAMM is a highly sensitive, molecular, high-resolution quantitative imaging approach. PMID:24231358

  16. Metabolic connectivity mapping reveals effective connectivity in the resting human brain

    PubMed Central

    Riedl, Valentin; Utz, Lukas; Castrillón, Gabriel; Grimmer, Timo; Rauschecker, Josef P.; Drzezga, Alexander; Sorg, Christian

    2016-01-01

    Directionality of signaling among brain regions provides essential information about human cognition and disease states. Assessing such effective connectivity (EC) across brain states using functional magnetic resonance imaging (fMRI) alone has proven difficult, however. We propose a novel measure of EC, termed metabolic connectivity mapping (MCM), that integrates undirected functional connectivity (FC) with local energy metabolism from fMRI and positron emission tomography (PET) data acquired simultaneously. This method is based on the concept that most energy required for neuronal communication is consumed postsynaptically, i.e., at the target neurons. We investigated MCM and possible changes in EC within the physiological range using “eyes open” versus “eyes closed” conditions in healthy subjects. Independent of condition, MCM reliably detected stable and bidirectional communication between early and higher visual regions. Moreover, we found stable top-down signaling from a frontoparietal network including frontal eye fields. In contrast, we found additional top-down signaling from all major clusters of the salience network to early visual cortex only in the eyes open condition. MCM revealed consistent bidirectional and unidirectional signaling across the entire cortex, along with prominent changes in network interactions across two simple brain states. We propose MCM as a novel approach for inferring EC from neuronal energy metabolism that is ideally suited to study signaling hierarchies in the brain and their defects in brain disorders. PMID:26712010

  17. Magnetic resonance volumetry reveals focal brain atrophy in transient epileptic amnesia.

    PubMed

    Butler, Christopher; van Erp, Willemijn; Bhaduri, Amit; Hammers, Alexander; Heckemann, Rolf; Zeman, Adam

    2013-09-01

    Transient epileptic amnesia (TEA) is a recently described epilepsy syndrome characterized by recurrent episodes of isolated memory loss. It is associated with two unusual forms of interictal memory impairment: accelerated long-term forgetting (ALF) and autobiographical amnesia. We investigated the neural basis of TEA using manual volumetry and automated multi-atlas-based segmentation of whole-brain magnetic resonance imaging data from 40 patients with TEA and 20 healthy controls. Both methods confirmed the presence of subtle, bilateral hippocampal atrophy. Additional atrophy was revealed in perirhinal and orbitofrontal cortices. The volumes of these regions correlated with anterograde memory performance. No structural correlates were found for ALF or autobiographical amnesia. The results support the hypothesis that TEA is a focal medial temporal lobe epilepsy syndrome but reveal additional pathology in connected brain regions. The unusual interictal memory deficits of TEA remain unexplained by structural pathology and may reflect physiological disruption of memory networks by subclinical epileptiform activity.

  18. Interspecies activity correlations reveal functional correspondence between monkey and human brain areas.

    PubMed

    Mantini, Dante; Hasson, Uri; Betti, Viviana; Perrucci, Mauro G; Romani, Gian Luca; Corbetta, Maurizio; Orban, Guy A; Vanduffel, Wim

    2012-02-05

    Evolution-driven functional changes in the primate brain are typically assessed by aligning monkey and human activation maps using cortical surface expansion models. These models use putative homologous areas as registration landmarks, assuming they are functionally correspondent. For cases in which functional changes have occurred in an area, this assumption prohibits to reveal whether other areas may have assumed lost functions. Here we describe a method to examine functional correspondences across species. Without making spatial assumptions, we assessed similarities in sensory-driven functional magnetic resonance imaging responses between monkey (Macaca mulatta) and human brain areas by temporal correlation. Using natural vision data, we revealed regions for which functional processing has shifted to topologically divergent locations during evolution. We conclude that substantial evolution-driven functional reorganizations have occurred, not always consistent with cortical expansion processes. This framework for evaluating changes in functional architecture is crucial to building more accurate evolutionary models.

  19. The Biology Of Physics: What The Brain Reveals About Our Understanding Of The Physical World

    NASA Astrophysics Data System (ADS)

    Dunbar, Kevin Niall

    2009-11-01

    Fundamental concepts in physics such as Newtonian mechanics are surprisingly difficult to learn and discover. Over the past decade have been using an educational neuroscience approach to science education using a combination of ecologically naturalistic situations, classroom settings, and neuroimaging methodologies to investigate the different ways that scientific concepts are invoked or activated in different contexts. In particular, we have sought to determine how networks of brain regions that are highly sensitive to features of the context in which they are used are involved in the use of scientific concepts. We have found that some concepts in physics that are highly tuned to perception are often inhibited in experts (with increased activations in error detection and inhibitory networks of the prefrontal cortex) rather than having undergone a wholesale conceptual reorganization. Other, concepts, such as those involved in perceptual causality can activate highly diverse brain regions, depending on task instructions. For example, when students are shown movies of balls colliding, we find increased activation in the right parietal lobe, yet when the students see the exact same movies and are told that these are positively charged particles repulsing we find increased activations in the temporal lobe that is consistent with the students retrieving semantic information. We also see similar see similar changes in activation patterns in students learning about phase shifts in chemistry classes. A key component of both students and scientists' discourse and reasoning is analogical thinking. Our recent fMRI work indicates that categorization is a key component of this type of reasoning that helps bind superficially different concepts together in the service of reasoning about the causes of unexpected findings. Taken together, these results are allowing us to make insights into the contextually relevant networks of knowledge that are activated during learning. This work

  20. Evans Blue Staining Reveals Vascular Leakage Associated with Focal Areas of Host-Parasite Interaction in Brains of Pigs Infected with Taenia solium

    PubMed Central

    Paredes, Adriana; Cangalaya, Carla; Rivera, Andrea; Gonzalez, Armando E.; Mahanty, Siddhartha; Garcia, Hector H.; Nash, Theodore E.

    2014-01-01

    Cysticidal drug treatment of viable Taenia solium brain parenchymal cysts leads to an acute pericystic host inflammatory response and blood brain barrier breakdown (BBB), commonly resulting in seizures. Naturally infected pigs, untreated or treated one time with praziquantel were sacrificed at 48 hr and 120 hr following the injection of Evans blue (EB) to assess the effect of treatment on larval parasites and surrounding tissue. Examination of harvested non encapsulated muscle cysts unexpectedly revealed one or more small, focal round region(s) of Evans blue dye infiltration (REBI) on the surface of otherwise non dye-stained muscle cysts. Histopathological analysis of REBI revealed focal areas of eosinophil-rich inflammatory infiltrates that migrated from the capsule into the tegument and internal structures of the parasite. In addition some encapsulated brain cysts, in which the presence of REBI could not be directly assessed, showed histopathology identical to that of the REBI. Muscle cysts with REBI were more frequent in pigs that had received praziquantel (6.6% of 3736 cysts; n = 6 pigs) than in those that were untreated (0.2% of 3172 cysts; n = 2 pigs). Similar results were found in the brain, where 20.7% of 29 cysts showed histopathology identical to muscle REBI cysts in praziquantel-treated pigs compared to the 4.3% of 47 cysts in untreated pigs. Closer examination of REBI infiltrates showed that EB was taken up only by eosinophils, a major component of the cellular infiltrates, which likely explains persistence of EB in the REBI. REBI likely represent early damaging host responses to T. solium cysts and highlight the focal nature of this initial host response and the importance of eosinophils at sites of host-parasite interaction. These findings suggest new avenues for immunomodulation to reduce inflammatory side effects of anthelmintic therapy. PMID:24915533

  1. Revealing pathologies in the liquid crystalline structures of the brain by polarimetric studies (Presentation Recording)

    NASA Astrophysics Data System (ADS)

    Bakhshetyan, Karen; Melkonyan, Gurgen G.; Galstian, Tigran V.; Saghatelyan, Armen

    2015-10-01

    Natural or "self" alignment of molecular complexes in living tissue represents many similarities with liquid crystals (LC), which are anisotropic liquids. The orientational characteristics of those complexes may be related to many important functional parameters and their study may reveal important pathologies. The know-how, accumulated thanks to the study of LC materials, may thus be used to this end. One of the traditionally used methods, to characterize those materials, is the polarized light imaging (PLI) that allows for label-free analysis of anisotropic structures in the brain tissue and can be used, for example, for the analysis of myelinated fiber bundles. In the current work, we first attempted to apply the PLI on the mouse histological brain sections to create a map of anisotropic structures using cross-polarizer transmission light. Then we implemented the PLI for comparative study of histological sections of human postmortem brain samples under normal and pathological conditions, such as Parkinson's disease (PD). Imaging the coronal, sagittal and horizontal sections of mouse brain allowed us to create a false color-coded fiber orientation map under polarized light. In human brain datasets for both control and PD groups we measured the pixel intensities in myelin-rich subregions of internal capsule and normalized these to non-myelinated background signal from putamen and caudate nucleus. Quantification of intensities revealed a statistically significant reduction of fiber intensity of PD compared to control subjects (2.801 +/- 0.303 and 3.724 +/- 0.07 respectively; *p < 0.05). Our study confirms the validity of PLI method for visualizing myelinated axonal fibers. This relatively simple technique can become a promising tool for study of neurodegenerative diseases where labeling-free imaging is an important benefit.

  2. Cloning of opal suppressor tRNA genes of a filamentous fungus reveals two tRNASerUGA genes with unexpected structural differences.

    PubMed Central

    Debuchy, R; Brygoo, Y

    1985-01-01

    The informational suppressors su4-1 and su8-1 of Podospora anserina were isolated by transformation of Schizosaccharomyces pombe UGA mutants. The DNA sequence revealed that they were opal (UGA) suppressor tRNAs. Wild-type alleles were also isolated by hybridization. The DNA sequence showed that they both encode species of tRNASerUGA. The gene SU8 has an 18-bp intervening sequence and its primary sequence is very different from that of SU4. PMID:3937728

  3. Genome-wide expression profiling in the Drosophila eye reveals unexpected repression of Notch signaling by the JAK/STAT pathway

    PubMed Central

    Flaherty, Maria Sol; Zavadil, Jiri; Ekas, Laura A.; Bach, Erika A.

    2010-01-01

    Although the JAK/STAT pathway regulates numerous processes in vertebrates and invertebrates through modulating transcription, its functionally-relevant transcriptional targets remain largely unknown. With one jak and one stat (stat92E), Drosophila provides a powerful system for finding new JAK/STAT target genes. Genome-wide expression profiling on eye discs in which Stat92E is hyperactivated, revealed 584 differentially-regulated genes, including known targets domeless, socs36E and wingless. Other differentially-regulated genes (chinmo, lama, Mo25, Imp-L2, Serrate, Delta) were validated and may represent new Stat92E targets. Genetic experiments revealed that Stat92E cell-autonomously represses Serrate, which encodes a Notch ligand. Loss of Stat92E led to de-repression of Serrate in the dorsal eye, resulting in ectopic Notch signaling and aberrant eye growth there. Thus, our micro-array documents a new Stat92E target gene and a previously-unidentified inhibitory action of Stat92E on Notch signaling. These data suggest that this study will be a useful resource for the identification of additional Stat92E targets. PMID:19504457

  4. Unexpected development of artistic talents

    PubMed Central

    Gordon, N

    2005-01-01

    The development of exceptional and unexpected artistic skills at any age must be a matter of curiosity. This can occur among young children with severe learning difficulties, especially if they are autistic. Some examples of these so called idiot-savants are given, and the way in which their brains may function. It is also true that elderly people who suffer from frontotemporal dementia can find that they are able to express themselves in remarkable art forms. This can occur in other types of dementia, but then more often it is the changes that result in the paintings of established artists, for example in the paintings of de Kooning. Possible links between these two phenomenon are discussed, and it is suggested that in both instances it may be that if the brain is relieved of a number of functions it can concentrate on the remaining ones. Ways in which this may operate in both groups are reviewed. PMID:16344297

  5. Revealing the cerebral regions and networks mediating vulnerability to depression: oxidative metabolism mapping of rat brain.

    PubMed

    Harro, Jaanus; Kanarik, Margus; Kaart, Tanel; Matrov, Denis; Kõiv, Kadri; Mällo, Tanel; Del Río, Joaquin; Tordera, Rosa M; Ramirez, Maria J

    2014-07-01

    The large variety of available animal models has revealed much on the neurobiology of depression, but each model appears as specific to a significant extent, and distinction between stress response, pathogenesis of depression and underlying vulnerability is difficult to make. Evidence from epidemiological studies suggests that depression occurs in biologically predisposed subjects under impact of adverse life events. We applied the diathesis-stress concept to reveal brain regions and functional networks that mediate vulnerability to depression and response to chronic stress by collapsing data on cerebral long term neuronal activity as measured by cytochrome c oxidase histochemistry in distinct animal models. Rats were rendered vulnerable to depression either by partial serotonergic lesion or by maternal deprivation, or selected for a vulnerable phenotype (low positive affect, low novelty-related activity or high hedonic response). Environmental adversity was brought about by applying chronic variable stress or chronic social defeat. Several brain regions, most significantly median raphe, habenula, retrosplenial cortex and reticular thalamus, were universally implicated in long-term metabolic stress response, vulnerability to depression, or both. Vulnerability was associated with higher oxidative metabolism levels as compared to resilience to chronic stress. Chronic stress, in contrast, had three distinct patterns of effect on oxidative metabolism in vulnerable vs. resilient animals. In general, associations between regional activities in several brain circuits were strongest in vulnerable animals, and chronic stress disrupted this interrelatedness. These findings highlight networks that underlie resilience to stress, and the distinct response to stress that occurs in vulnerable subjects.

  6. Cerebrospinal Fluid Proteomics Reveals Potential Pathogenic Changes in the Brains of SIV-infected Monkeys

    PubMed Central

    Pendyala, Gurudutt; Trauger, Sunia A.; Kalisiak, Ewa; Ellis, Ronald J.; Siuzdak, Gary; Fox, Howard S.

    2009-01-01

    The HIV-1-associated neurocognitive disorder occurs in approximately one-third of infected individuals. It has persisted in the current era of anti-retroviral therapy, and its study is complicated by the lack of biomarkers for this condition. Since the cerebrospinal fluid is the most proximal biofluid to the site of pathology, we studied the cerebrospinal fluid in a nonhuman primate model for HIV-1-associated neurocognitive disorder. Here we present a simple and efficient liquid chromatography coupled mass spectrometry based proteomics approach that utilizes small amounts of cerebrospinal fluid. First, we demonstrate the validity of the methodology using human cerebrospinal fluid. Next, using the simian immunodeficiency virus infected monkey model, we show its efficacy in identifying proteins such as alpha-1-antitrypsin, complement C3, hemopexin, IgM heavy chain and plasminogen, whose increased expression is linked to disease. Finally, we find that the increase in cerebrospinal fluid proteins is linked to increased expression of their genes in the brain parenchyma, revealing that the cerebrospinal fluid alterations identified reflect changes in the brain itself and not merely leakage of the blood-brain or blood- cerebrospinal fluid barriers. This study reveals new central nervous system alterations in lentivirus-induced neurological disease, and this technique can be applied to other systems in which limited amounts of biofluids can be obtained. PMID:19281240

  7. Measurement of PIP3 Levels Reveals an Unexpected Role for p110β in Early Adaptive Responses to p110α-Specific Inhibitors in Luminal Breast Cancer

    PubMed Central

    Costa, Carlotta; Ebi, Hiromichi; Martini, Miriam; Beausoleil, Sean A.; Faber, Anthony C.; Jakubik, Charles T.; Huang, Alan; Wang, Youzhen; Nishtala, Madhuri; Hall, Ben; Rikova, Klarisa; Zhao, Jean; Hirsch, Emilio; Benes, Cyril H.

    2016-01-01

    SUMMARY BYL719, which selectively inhibits the alpha isoform of the phosphatidylinositol 3-kinase (PI3K) catalytic subunit (p110α), is currently in clinical trials for the treatment of solid tumors, especially luminal breast cancers with PIK3CA mutations and/or HER2 amplification. This study reveals that, even among these sensitive cancers, the initial efficacy of p110α inhibition is mitigated by rapid re-accumulation of the PI3K product PIP3 produced by the p110β isoform. Importantly, the reactivation of PI3K mediated by p110β does not invariably restore AKT phosphorylation, demonstrating the limitations of using phospho-AKT as a surrogate to measure PI3K activation. Consistently, we show that the addition of the p110β inhibitor to BYL719 prevents the PIP3 rebound and induces greater antitumor efficacy in HER2-amplified and PIK3CA mutant cancers. PMID:25544637

  8. Computerized three-dimensional reconstruction reveals cerebrovascular regulatory subregions in rat brain stem.

    PubMed

    Underwood, M D; Arango, V; Smith, R W; Bakalian, M J; Mann, J J

    1993-09-01

    Three-dimensional wireframe reconstructions were used to examine the relationship between the anatomical localization of electrode sites and the cerebrovascular response which was elicited by electrical stimulation of the dorsal raphe nucleus (DRN). Reconstructions of the rat brain and DRN were done from atlas plates and from Nissl-stained coronal sections (100-micron increments). Data points were entered and three-dimensional reconstructions were performed using commercially available software and a personal computer. Display of the entire brain yielded views which obscured visualization of the DRN. The data file was edited to reduce the number of contours without affecting the display resolution of the DRN. Selective display of the DRN and electronic rotation from the coronal to a sagittal view revealed a functional organization of the cerebral blood flow responses which was not apparent in two-dimensional coronal sections.

  9. The organization of thinking: what functional brain imaging reveals about the neuroarchitecture of complex cognition.

    PubMed

    Just, Marcel Adam; Varma, Sashank

    2007-09-01

    Recent findings in brain imaging, particularly in fMRI, are beginning to reveal some of the fundamental properties of the organization of the cortical systems that underpin complex cognition. We propose an emerging set of operating principles that govern this organization, characterizing the system as a set of collaborating cortical centers that operate as a large-scale cortical network. Two of the network's critical features are that it is resource constrained and dynamically configured, with resource constraints and demands dynamically shaping the network topology. The operating principles are embodied in a cognitive neuroarchitecture, 4CAPS, consisting of a number of interacting computational centers that correspond to activating cortical areas. Each 4CAPS center is a hybrid production system, possessing both symbolic and connectionist attributes. We describe 4CAPS models of sentence comprehension, spatial problem solving, and complex multitasking and compare the accounts of these models with brain activation and behavioral results. Finally, we compare 4CAPS with other proposed neuroarchitectures.

  10. Insights into the metabolic response to traumatic brain injury as revealed by 13C NMR spectroscopy

    PubMed Central

    Bartnik-Olson, Brenda L.; Harris, Neil G.; Shijo, Katsunori; Sutton, Richard L.

    2013-01-01

    The present review highlights critical issues related to cerebral metabolism following traumatic brain injury (TBI) and the use of 13C labeled substrates and nuclear magnetic resonance (NMR) spectroscopy to study these changes. First we address some pathophysiologic factors contributing to metabolic dysfunction following TBI. We then examine how 13C NMR spectroscopy strategies have been used to investigate energy metabolism, neurotransmission, the intracellular redox state, and neuroglial compartmentation following injury. 13C NMR spectroscopy studies of brain extracts from animal models of TBI have revealed enhanced glycolytic production of lactate, evidence of pentose phosphate pathway (PPP) activation, and alterations in neuronal and astrocyte oxidative metabolism that are dependent on injury severity. Differential incorporation of label into glutamate and glutamine from 13C labeled glucose or acetate also suggest TBI-induced adaptations to the glutamate-glutamine cycle. PMID:24109452

  11. Intact-Brain Analyses Reveal Distinct Information Carried by SNc Dopamine Subcircuits.

    PubMed

    Lerner, Talia N; Shilyansky, Carrie; Davidson, Thomas J; Evans, Kathryn E; Beier, Kevin T; Zalocusky, Kelly A; Crow, Ailey K; Malenka, Robert C; Luo, Liqun; Tomer, Raju; Deisseroth, Karl

    2015-07-30

    Recent progress in understanding the diversity of midbrain dopamine neurons has highlighted the importance--and the challenges--of defining mammalian neuronal cell types. Although neurons may be best categorized using inclusive criteria spanning biophysical properties, wiring of inputs, wiring of outputs, and activity during behavior, linking all of these measurements to cell types within the intact brains of living mammals has been difficult. Here, using an array of intact-brain circuit interrogation tools, including CLARITY, COLM, optogenetics, viral tracing, and fiber photometry, we explore the diversity of dopamine neurons within the substantia nigra pars compacta (SNc). We identify two parallel nigrostriatal dopamine neuron subpopulations differing in biophysical properties, input wiring, output wiring to dorsomedial striatum (DMS) versus dorsolateral striatum (DLS), and natural activity patterns during free behavior. Our results reveal independently operating nigrostriatal information streams, with implications for understanding the logic of dopaminergic feedback circuits and the diversity of mammalian neuronal cell types.

  12. Severe Left Ventricular Hypertrophy, Small Pericardial Effusion, and Diffuse Late Gadolinium Enhancement by Cardiac Magnetic Resonance Suspecting Cardiac Amyloidosis: Endomyocardial Biopsy Reveals an Unexpected Diagnosis

    PubMed Central

    Hofmann, Nina P.; Giusca, Sorin; Klingel, Karin; Nunninger, Peter; Korosoglou, Grigorios

    2016-01-01

    Left ventricular (LV) hypertrophy can be related to a multitude of cardiac disorders, such as hypertrophic cardiomyopathy (HCM), cardiac amyloidosis, and hypertensive heart disease. Although the presence of LV hypertrophy is generally associated with poorer cardiac outcomes, the early differentiation between these pathologies is crucial due to the presence of specific treatment options. The diagnostic process with LV hypertrophy requires the integration of clinical evaluation, electrocardiography (ECG), echocardiography, biochemical markers, and if required CMR and endomyocardial biopsy in order to reach the correct diagnosis. Here, we present a case of a patient with severe LV hypertrophy (septal wall thickness of 23 mm, LV mass of 264 g, and LV mass index of 147 g/m2), severely impaired longitudinal function, and preserved radial contractility (ejection fraction = 55%), accompanied by small pericardial effusion and diffuse late gadolinium enhancement (LGE) by cardiac magnetic resonance (CMR). Due to the imaging findings, an infiltrative cardiomyopathy, such as cardiac amyloidosis, was suspected. However, amyloid accumulation was excluded by endomyocardial biopsy, which revealed the presence of diffuse myocardial fibrosis in an advanced hypertensive heart disease. PMID:27247807

  13. Brain responses in humans reveal ideal observer-like sensitivity to complex acoustic patterns

    PubMed Central

    Pearce, Marcus T.; Griffiths, Timothy D.; Chait, Maria

    2016-01-01

    We use behavioral methods, magnetoencephalography, and functional MRI to investigate how human listeners discover temporal patterns and statistical regularities in complex sound sequences. Sensitivity to patterns is fundamental to sensory processing, in particular in the auditory system, because most auditory signals only have meaning as successions over time. Previous evidence suggests that the brain is tuned to the statistics of sensory stimulation. However, the process through which this arises has been elusive. We demonstrate that listeners are remarkably sensitive to the emergence of complex patterns within rapidly evolving sound sequences, performing on par with an ideal observer model. Brain responses reveal online processes of evidence accumulation—dynamic changes in tonic activity precisely correlate with the expected precision or predictability of ongoing auditory input—both in terms of deterministic (first-order) structure and the entropy of random sequences. Source analysis demonstrates an interaction between primary auditory cortex, hippocampus, and inferior frontal gyrus in the process of discovering the regularity within the ongoing sound sequence. The results are consistent with precision based predictive coding accounts of perceptual inference and provide compelling neurophysiological evidence of the brain's capacity to encode high-order temporal structure in sensory signals. PMID:26787854

  14. Brain responses in humans reveal ideal observer-like sensitivity to complex acoustic patterns.

    PubMed

    Barascud, Nicolas; Pearce, Marcus T; Griffiths, Timothy D; Friston, Karl J; Chait, Maria

    2016-02-01

    We use behavioral methods, magnetoencephalography, and functional MRI to investigate how human listeners discover temporal patterns and statistical regularities in complex sound sequences. Sensitivity to patterns is fundamental to sensory processing, in particular in the auditory system, because most auditory signals only have meaning as successions over time. Previous evidence suggests that the brain is tuned to the statistics of sensory stimulation. However, the process through which this arises has been elusive. We demonstrate that listeners are remarkably sensitive to the emergence of complex patterns within rapidly evolving sound sequences, performing on par with an ideal observer model. Brain responses reveal online processes of evidence accumulation--dynamic changes in tonic activity precisely correlate with the expected precision or predictability of ongoing auditory input--both in terms of deterministic (first-order) structure and the entropy of random sequences. Source analysis demonstrates an interaction between primary auditory cortex, hippocampus, and inferior frontal gyrus in the process of discovering the regularity within the ongoing sound sequence. The results are consistent with precision based predictive coding accounts of perceptual inference and provide compelling neurophysiological evidence of the brain's capacity to encode high-order temporal structure in sensory signals.

  15. Neural correlates of apathy revealed by lesion mapping in participants with traumatic brain injuries.

    PubMed

    Knutson, Kristine M; Monte, Olga Dal; Raymont, Vanessa; Wassermann, Eric M; Krueger, Frank; Grafman, Jordan

    2014-03-01

    Apathy, common in neurological disorders, is defined as disinterest and loss of motivation, with a reduction in self-initiated activity. Research in diseased populations has shown that apathy is associated with variations in the volume of brain regions such as the anterior cingulate and the frontal lobes. The goal of this study was to determine the neural signatures of apathy in people with penetrating traumatic brain injuries (pTBIs), as to our knowledge, these have not been studied in this sample. We studied 176 male Vietnam War veterans with pTBIs using voxel-based lesion-symptom mapping (VLSM) and apathy scores from the UCLA Neuropsychiatric Inventory (NPI), a structured inventory of symptoms completed by a caregiver. Our results revealed that increased apathy symptoms were associated with brain damage in limbic and cortical areas of the left hemisphere including the anterior cingulate, inferior, middle, and superior frontal regions, insula, and supplementary motor area. Our results are consistent with the literature, and extend them to people with focal pTBI. Apathy is a significant symptom since it can reduce participation of the patient in family and other social interactions, and diminish affective decision-making. PMID:23404730

  16. Neural correlates of apathy revealed by lesion mapping in participants with traumatic brain injuries.

    PubMed

    Knutson, Kristine M; Monte, Olga Dal; Raymont, Vanessa; Wassermann, Eric M; Krueger, Frank; Grafman, Jordan

    2014-03-01

    Apathy, common in neurological disorders, is defined as disinterest and loss of motivation, with a reduction in self-initiated activity. Research in diseased populations has shown that apathy is associated with variations in the volume of brain regions such as the anterior cingulate and the frontal lobes. The goal of this study was to determine the neural signatures of apathy in people with penetrating traumatic brain injuries (pTBIs), as to our knowledge, these have not been studied in this sample. We studied 176 male Vietnam War veterans with pTBIs using voxel-based lesion-symptom mapping (VLSM) and apathy scores from the UCLA Neuropsychiatric Inventory (NPI), a structured inventory of symptoms completed by a caregiver. Our results revealed that increased apathy symptoms were associated with brain damage in limbic and cortical areas of the left hemisphere including the anterior cingulate, inferior, middle, and superior frontal regions, insula, and supplementary motor area. Our results are consistent with the literature, and extend them to people with focal pTBI. Apathy is a significant symptom since it can reduce participation of the patient in family and other social interactions, and diminish affective decision-making.

  17. Unexpectedly high affinity of a novel histamine H3 receptor antagonist, GSK239512, in vivo in human brain, determined using PET

    PubMed Central

    Ashworth, S; Berges, A; Rabiner, E A; Wilson, A A; Comley, R A; Lai, R Y K; Boardley, R; Searle, G; Gunn, R N; Laruelle, M; Cunningham, V J

    2014-01-01

    BACKGROUND AND PURPOSE This study aimed to investigate the relationship between the plasma concentration (PK) of the novel histamine H3 receptor antagonist, GSK239512, and the brain occupancy of H3 receptors (RO) in healthy human volunteers. EXPERIMENTAL APPROACH PET scans were obtained after i.v. administration of the H3-specific radioligand [11C]GSK189254. Each subject was scanned before and after single oral doses of GSK239512, at 4 and 24 h after dose. PET data were analysed by compartmental analysis, and regional RO estimates were obtained by graphical analysis of changes in the total volumes of distribution of the radioligand, followed by a correction for occupancy by the high affinity radioligand. The PK/RO relationship was analysed by a population-modelling approach, using the average PK of GSK239512 during each scan. KEY RESULTS Following administration of GSK239512, there was a reduction in the brain uptake of [11C]GSK189254 in all regions, including cerebellum. RO at 4 h was higher than at 24 h, and the PK/RO model estimated a PK associated with 50% of RO of 0.0068 ng·mL−1. This corresponds to a free concentration of 4.50 × 10−12 M (pK = 11.3). CONCLUSIONS AND IMPLICATIONS The affinity of GSK239512 for brain H3 receptors in humans in vivo is much higher than that expected from studies in vitro, and higher than that observed in PET studies in pigs. The study illustrates the utility of carrying out PET studies in humans early in drug development, providing accurate quantification of GSK239512 RO in vivo as a function of time and dose. PMID:24670146

  18. A functional genomics screen in planarians reveals regulators of whole-brain regeneration

    PubMed Central

    Roberts-Galbraith, Rachel H; Brubacher, John L; Newmark, Phillip A

    2016-01-01

    Planarians regenerate all body parts after injury, including the central nervous system (CNS). We capitalized on this distinctive trait and completed a gene expression-guided functional screen to identify factors that regulate diverse aspects of neural regeneration in Schmidtea mediterranea. Our screen revealed molecules that influence neural cell fates, support the formation of a major connective hub, and promote reestablishment of chemosensory behavior. We also identified genes that encode signaling molecules with roles in head regeneration, including some that are produced in a previously uncharacterized parenchymal population of cells. Finally, we explored genes downregulated during planarian regeneration and characterized, for the first time, glial cells in the planarian CNS that respond to injury by repressing several transcripts. Collectively, our studies revealed diverse molecules and cell types that underlie an animal’s ability to regenerate its brain. DOI: http://dx.doi.org/10.7554/eLife.17002.001 PMID:27612384

  19. Transcriptional profiling reveals that C5a alters microRNA in brain endothelial cells

    PubMed Central

    Eadon, Michael T; Jacob, Alexander; Cunningham, Patrick N; Quigg, Richard J; Garcia, Joe G N; Alexander, Jessy J

    2014-01-01

    Blood–brain barrier (BBB) disturbance is a crucial occurrence in many neurological diseases, including systemic lupus erythematosus (SLE). Our previous studies showed that experimental lupus serum altered the integrity of the mouse brain endothelial layer, an important constituent of the BBB. Complement activation occurs in lupus with increased circulating complement components. Using a genomics approach, we identified the microRNA (miRNA) altered in mouse brain endothelial cells (bEnd3) by lupus serum and the complement protein, C5a. Of the 318 miRNA evaluated, 23 miRNAs were altered by lupus serum and 32 were altered by C5a alone compared with controls. Seven miRNAs (P < 0·05) were differentially expressed by both treatments: mmu-miR-133a*, mmu-miR-193*, mmu-miR-26b, mmu-miR-28*, mmu-miR-320a, mmu-miR-423-3p and mmu-miR-509-5p. The microarray results were validated by quantitative RT-PCR. In line with the in vitro results, expression of miR-26b and miR-28* were also significantly up-regulated in lupus mouse brain which was reduced by C5a receptor inhibition. Target prediction analysis revealed miR gene targets encoding components involved in inflammation, matrix arrangement, and apoptosis, pathways known to play important roles in central nervous system lupus. Our findings suggest that the miRNAs reported in this study may represent novel therapeutic targets in central nervous system lupus and other similar neuroinflammatory settings. PMID:24801999

  20. Transcriptional profiling reveals that C5a alters microRNA in brain endothelial cells.

    PubMed

    Eadon, Michael T; Jacob, Alexander; Cunningham, Patrick N; Quigg, Richard J; Garcia, Joe G N; Alexander, Jessy J

    2014-11-01

    Blood-brain barrier (BBB) disturbance is a crucial occurrence in many neurological diseases, including systemic lupus erythematosus (SLE). Our previous studies showed that experimental lupus serum altered the integrity of the mouse brain endothelial layer, an important constituent of the BBB. Complement activation occurs in lupus with increased circulating complement components. Using a genomics approach, we identified the microRNA (miRNA) altered in mouse brain endothelial cells (bEnd3) by lupus serum and the complement protein, C5a. Of the 318 miRNA evaluated, 23 miRNAs were altered by lupus serum and 32 were altered by C5a alone compared with controls. Seven miRNAs (P < 0 · 05) were differentially expressed by both treatments: mmu-miR-133a*, mmu-miR-193*, mmu-miR-26b, mmu-miR-28*, mmu-miR-320a, mmu-miR-423-3p and mmu-miR-509-5p. The microarray results were validated by quantitative RT-PCR. In line with the in vitro results, expression of miR-26b and miR-28* were also significantly up-regulated in lupus mouse brain which was reduced by C5a receptor inhibition. Target prediction analysis revealed miR gene targets encoding components involved in inflammation, matrix arrangement, and apoptosis, pathways known to play important roles in central nervous system lupus. Our findings suggest that the miRNAs reported in this study may represent novel therapeutic targets in central nervous system lupus and other similar neuroinflammatory settings.

  1. Transcriptional profiling reveals that C5a alters microRNA in brain endothelial cells.

    PubMed

    Eadon, Michael T; Jacob, Alexander; Cunningham, Patrick N; Quigg, Richard J; Garcia, Joe G N; Alexander, Jessy J

    2014-11-01

    Blood-brain barrier (BBB) disturbance is a crucial occurrence in many neurological diseases, including systemic lupus erythematosus (SLE). Our previous studies showed that experimental lupus serum altered the integrity of the mouse brain endothelial layer, an important constituent of the BBB. Complement activation occurs in lupus with increased circulating complement components. Using a genomics approach, we identified the microRNA (miRNA) altered in mouse brain endothelial cells (bEnd3) by lupus serum and the complement protein, C5a. Of the 318 miRNA evaluated, 23 miRNAs were altered by lupus serum and 32 were altered by C5a alone compared with controls. Seven miRNAs (P < 0 · 05) were differentially expressed by both treatments: mmu-miR-133a*, mmu-miR-193*, mmu-miR-26b, mmu-miR-28*, mmu-miR-320a, mmu-miR-423-3p and mmu-miR-509-5p. The microarray results were validated by quantitative RT-PCR. In line with the in vitro results, expression of miR-26b and miR-28* were also significantly up-regulated in lupus mouse brain which was reduced by C5a receptor inhibition. Target prediction analysis revealed miR gene targets encoding components involved in inflammation, matrix arrangement, and apoptosis, pathways known to play important roles in central nervous system lupus. Our findings suggest that the miRNAs reported in this study may represent novel therapeutic targets in central nervous system lupus and other similar neuroinflammatory settings. PMID:24801999

  2. Dependency Network Analysis (DEPNA) Reveals Context Related Influence of Brain Network Nodes

    PubMed Central

    Jacob, Yael; Winetraub, Yonatan; Raz, Gal; Ben-Simon, Eti; Okon-Singer, Hadas; Rosenberg-Katz, Keren; Hendler, Talma; Ben-Jacob, Eshel

    2016-01-01

    Communication between and within brain regions is essential for information processing within functional networks. The current methods to determine the influence of one region on another are either based on temporal resolution, or require a predefined model for the connectivity direction. However these requirements are not always achieved, especially in fMRI studies, which have poor temporal resolution. We thus propose a new graph theory approach that focuses on the correlation influence between selected brain regions, entitled Dependency Network Analysis (DEPNA). Partial correlations are used to quantify the level of influence of each node during task performance. As a proof of concept, we conducted the DEPNA on simulated datasets and on two empirical motor and working memory fMRI tasks. The simulations revealed that the DEPNA correctly captures the network’s hierarchy of influence. Applying DEPNA to the functional tasks reveals the dynamics between specific nodes as would be expected from prior knowledge. To conclude, we demonstrate that DEPNA can capture the most influencing nodes in the network, as they emerge during specific cognitive processes. This ability opens a new horizon for example in delineating critical nodes for specific clinical interventions. PMID:27271458

  3. Unexpected response. Student essay

    SciTech Connect

    White, T.R.

    1985-05-08

    This paper reviews the NATO mission of deterrence and the threat of its use of nuclear weapons. It suggests that the threat is viable until a war starts, but then becomes meaningless because the Federal Republic of Germany would opt for a different course of action - its Unexpected Response. The conclusion is that convential forces are the essential deterrent given strategic parity. Then strategic mobility is addressed as it provides greater conventional reinforcement potential than generally assumed. An Unexpected Response by the Congress which could be counter-productive to the use of our new mobility is then discussed.

  4. K-shell decomposition reveals hierarchical cortical organization of the human brain

    NASA Astrophysics Data System (ADS)

    Lahav, Nir; Ksherim, Baruch; Ben-Simon, Eti; Maron-Katz, Adi; Cohen, Reuven; Havlin, Shlomo

    2016-08-01

    In recent years numerous attempts to understand the human brain were undertaken from a network point of view. A network framework takes into account the relationships between the different parts of the system and enables to examine how global and complex functions might emerge from network topology. Previous work revealed that the human brain features ‘small world’ characteristics and that cortical hubs tend to interconnect among themselves. However, in order to fully understand the topological structure of hubs, and how their profile reflect the brain’s global functional organization, one needs to go beyond the properties of a specific hub and examine the various structural layers that make up the network. To address this topic further, we applied an analysis known in statistical physics and network theory as k-shell decomposition analysis. The analysis was applied on a human cortical network, derived from MRI\\DSI data of six participants. Such analysis enables us to portray a detailed account of cortical connectivity focusing on different neighborhoods of inter-connected layers across the cortex. Our findings reveal that the human cortex is highly connected and efficient, and unlike the internet network contains no isolated nodes. The cortical network is comprised of a nucleus alongside shells of increasing connectivity that formed one connected giant component, revealing the human brain’s global functional organization. All these components were further categorized into three hierarchies in accordance with their connectivity profile, with each hierarchy reflecting different functional roles. Such a model may explain an efficient flow of information from the lowest hierarchy to the highest one, with each step enabling increased data integration. At the top, the highest hierarchy (the nucleus) serves as a global interconnected collective and demonstrates high correlation with consciousness related regions, suggesting that the nucleus might serve as a

  5. RNA Sequence Analysis of Human Huntington Disease Brain Reveals an Extensive Increase in Inflammatory and Developmental Gene Expression

    PubMed Central

    Labadorf, Adam; Hoss, Andrew G.; Lagomarsino, Valentina; Latourelle, Jeanne C.; Hadzi, Tiffany C.; Bregu, Joli; MacDonald, Marcy E.; Gusella, James F.; Chen, Jiang-Fan; Akbarian, Schahram; Weng, Zhiping; Myers, Richard H.

    2015-01-01

    Huntington’s Disease (HD) is a devastating neurodegenerative disorder that is caused by an expanded CAG trinucleotide repeat in the Huntingtin (HTT) gene. Transcriptional dysregulation in the human HD brain has been documented but is incompletely understood. Here we present a genome-wide analysis of mRNA expression in human prefrontal cortex from 20 HD and 49 neuropathologically normal controls using next generation high-throughput sequencing. Surprisingly, 19% (5,480) of the 28,087 confidently detected genes are differentially expressed (FDR<0.05) and are predominantly up-regulated. A novel hypothesis-free geneset enrichment method that dissects large gene lists into functionally and transcriptionally related groups discovers that the differentially expressed genes are enriched for immune response, neuroinflammation, and developmental genes. Markers for all major brain cell types are observed, suggesting that HD invokes a systemic response in the brain area studied. Unexpectedly, the most strongly differentially expressed genes are a homeotic gene set (represented by Hox and other homeobox genes), that are almost exclusively expressed in HD, a profile not widely implicated in HD pathogenesis. The significance of transcriptional changes of developmental processes in the HD brain is poorly understood and warrants further investigation. The role of inflammation and the significance of non-neuronal involvement in HD pathogenesis suggest anti-inflammatory therapeutics may offer important opportunities in treating HD. PMID:26636579

  6. ARTIFICIAL SELECTION ON RELATIVE BRAIN SIZE REVEALS A POSITIVE GENETIC CORRELATION BETWEEN BRAIN SIZE AND PROACTIVE PERSONALITY IN THE GUPPY

    PubMed Central

    Kotrschal, Alexander; Lievens, Eva JP; Dahlbom, Josefin; Bundsen, Andreas; Semenova, Svetlana; Sundvik, Maria; Maklakov, Alexei A; Winberg, Svante; Panula, Pertti; Kolm, Niclas; Morrow, E

    2014-01-01

    Animal personalities range from individuals that are shy, cautious, and easily stressed (a “reactive” personality type) to individuals that are bold, innovative, and quick to learn novel tasks, but also prone to routine formation (a “proactive” personality type). Although personality differences should have important consequences for fitness, their underlying mechanisms remain poorly understood. Here, we investigated how genetic variation in brain size affects personality. We put selection lines of large- and small-brained guppies (Poecilia reticulata), with known differences in cognitive ability, through three standard personality assays. First, we found that large-brained animals were faster to habituate to, and more exploratory in, open field tests. Large-brained females were also bolder. Second, large-brained animals excreted less cortisol in a stressful situation (confinement). Third, large-brained animals were slower to feed from a novel food source, which we interpret as being caused by reduced behavioral flexibility rather than lack of innovation in the large-brained lines. Overall, the results point toward a more proactive personality type in large-brained animals. Thus, this study provides the first experimental evidence linking brain size and personality, an interaction that may affect important fitness-related aspects of ecology such as dispersal and niche exploration. PMID:24359469

  7. Artificial selection on relative brain size reveals a positive genetic correlation between brain size and proactive personality in the guppy.

    PubMed

    Kotrschal, Alexander; Lievens, Eva J P; Dahlbom, Josefin; Bundsen, Andreas; Semenova, Svetlana; Sundvik, Maria; Maklakov, Alexei A; Winberg, Svante; Panula, Pertti; Kolm, Niclas

    2014-04-01

    Animal personalities range from individuals that are shy, cautious, and easily stressed (a "reactive" personality type) to individuals that are bold, innovative, and quick to learn novel tasks, but also prone to routine formation (a "proactive" personality type). Although personality differences should have important consequences for fitness, their underlying mechanisms remain poorly understood. Here, we investigated how genetic variation in brain size affects personality. We put selection lines of large- and small-brained guppies (Poecilia reticulata), with known differences in cognitive ability, through three standard personality assays. First, we found that large-brained animals were faster to habituate to, and more exploratory in, open field tests. Large-brained females were also bolder. Second, large-brained animals excreted less cortisol in a stressful situation (confinement). Third, large-brained animals were slower to feed from a novel food source, which we interpret as being caused by reduced behavioral flexibility rather than lack of innovation in the large-brained lines. Overall, the results point toward a more proactive personality type in large-brained animals. Thus, this study provides the first experimental evidence linking brain size and personality, an interaction that may affect important fitness-related aspects of ecology such as dispersal and niche exploration. PMID:24359469

  8. Lost for emotion words: What motor and limbic brain activity reveals about autism and semantic theory

    PubMed Central

    Moseley, Rachel L.; Shtyrov, Yury; Mohr, Bettina; Lombardo, Michael V.; Baron-Cohen, Simon; Pulvermüller, Friedemann

    2015-01-01

    Autism spectrum conditions (ASC) are characterised by deficits in understanding and expressing emotions and are frequently accompanied by alexithymia, a difficulty in understanding and expressing emotion words. Words are differentially represented in the brain according to their semantic category and these difficulties in ASC predict reduced activation to emotion-related words in limbic structures crucial for affective processing. Semantic theories view ‘emotion actions’ as critical for learning the semantic relationship between a word and the emotion it describes, such that emotion words typically activate the cortical motor systems involved in expressing emotion actions such as facial expressions. As ASC are also characterised by motor deficits and atypical brain structure and function in these regions, motor structures would also be expected to show reduced activation during emotion-semantic processing. Here we used event-related fMRI to compare passive processing of emotion words in comparison to abstract verbs and animal names in typically-developing controls and individuals with ASC. Relatively reduced brain activation in ASC for emotion words, but not matched control words, was found in motor areas and cingulate cortex specifically. The degree of activation evoked by emotion words in the motor system was also associated with the extent of autistic traits as revealed by the Autism Spectrum Quotient. We suggest that hypoactivation of motor and limbic regions for emotion word processing may underlie difficulties in processing emotional language in ASC. The role that sensorimotor systems and their connections might play in the affective and social-communication difficulties in ASC is discussed. PMID:25278250

  9. Lost for emotion words: what motor and limbic brain activity reveals about autism and semantic theory.

    PubMed

    Moseley, Rachel L; Shtyrov, Yury; Mohr, Bettina; Lombardo, Michael V; Baron-Cohen, Simon; Pulvermüller, Friedemann

    2015-01-01

    Autism spectrum conditions (ASC) are characterised by deficits in understanding and expressing emotions and are frequently accompanied by alexithymia, a difficulty in understanding and expressing emotion words. Words are differentially represented in the brain according to their semantic category and these difficulties in ASC predict reduced activation to emotion-related words in limbic structures crucial for affective processing. Semantic theories view 'emotion actions' as critical for learning the semantic relationship between a word and the emotion it describes, such that emotion words typically activate the cortical motor systems involved in expressing emotion actions such as facial expressions. As ASC are also characterised by motor deficits and atypical brain structure and function in these regions, motor structures would also be expected to show reduced activation during emotion-semantic processing. Here we used event-related fMRI to compare passive processing of emotion words in comparison to abstract verbs and animal names in typically-developing controls and individuals with ASC. Relatively reduced brain activation in ASC for emotion words, but not matched control words, was found in motor areas and cingulate cortex specifically. The degree of activation evoked by emotion words in the motor system was also associated with the extent of autistic traits as revealed by the Autism Spectrum Quotient. We suggest that hypoactivation of motor and limbic regions for emotion word processing may underlie difficulties in processing emotional language in ASC. The role that sensorimotor systems and their connections might play in the affective and social-communication difficulties in ASC is discussed.

  10. Proteomic Profiling in the Brain of CLN1 Disease Model Reveals Affected Functional Modules.

    PubMed

    Tikka, Saara; Monogioudi, Evanthia; Gotsopoulos, Athanasios; Soliymani, Rabah; Pezzini, Francesco; Scifo, Enzo; Uusi-Rauva, Kristiina; Tyynelä, Jaana; Baumann, Marc; Jalanko, Anu; Simonati, Alessandro; Lalowski, Maciej

    2016-03-01

    Neuronal ceroid lipofuscinoses (NCL) are the most commonly inherited progressive encephalopathies of childhood. Pathologically, they are characterized by endolysosomal storage with different ultrastructural features and biochemical compositions. The molecular mechanisms causing progressive neurodegeneration and common molecular pathways linking expression of different NCL genes are largely unknown. We analyzed proteome alterations in the brains of a mouse model of human infantile CLN1 disease-palmitoyl-protein thioesterase 1 (Ppt1) gene knockout and its wild-type age-matched counterpart at different stages: pre-symptomatic, symptomatic and advanced. For this purpose, we utilized a combination of laser capture microdissection-based quantitative liquid chromatography tandem mass spectrometry (MS) and matrix-assisted laser desorption/ionization time-of-flight MS imaging to quantify/visualize the changes in protein expression in disease-affected brain thalamus and cerebral cortex tissue slices, respectively. Proteomic profiling of the pre-symptomatic stage thalamus revealed alterations mostly in metabolic processes and inhibition of various neuronal functions, i.e., neuritogenesis. Down-regulation in dynamics associated with growth of plasma projections and cellular protrusions was further corroborated by findings from RNA sequencing of CLN1 patients' fibroblasts. Changes detected at the symptomatic stage included: mitochondrial functions, synaptic vesicle transport, myelin proteome and signaling cascades, such as RhoA signaling. Considerable dysregulation of processes related to mitochondrial cell death, RhoA/Huntington's disease signaling and myelin sheath breakdown were observed at the advanced stage of the disease. The identified changes in protein levels were further substantiated by bioinformatics and network approaches, immunohistochemistry on brain tissues and literature knowledge, thus identifying various functional modules affected in the CLN1 childhood

  11. Systems-based analyses of brain regions functionally impacted in Parkinson's disease reveals underlying causal mechanisms.

    PubMed

    Riley, Brigit E; Gardai, Shyra J; Emig-Agius, Dorothea; Bessarabova, Marina; Ivliev, Alexander E; Schüle, Birgitt; Schüle, Birgit; Alexander, Jeff; Wallace, William; Halliday, Glenda M; Langston, J William; Braxton, Scott; Yednock, Ted; Shaler, Thomas; Johnston, Jennifer A

    2014-01-01

    Detailed analysis of disease-affected tissue provides insight into molecular mechanisms contributing to pathogenesis. Substantia nigra, striatum, and cortex are functionally connected with increasing degrees of alpha-synuclein pathology in Parkinson's disease. We undertook functional and causal pathway analysis of gene expression and proteomic alterations in these three regions, and the data revealed pathways that correlated with disease progression. In addition, microarray and RNAseq experiments revealed previously unidentified causal changes related to oligodendrocyte function and synaptic vesicle release, and these and other changes were reflected across all brain regions. Importantly, subsets of these changes were replicated in Parkinson's disease blood; suggesting peripheral tissue may provide important avenues for understanding and measuring disease status and progression. Proteomic assessment revealed alterations in mitochondria and vesicular transport proteins that preceded gene expression changes indicating defects in translation and/or protein turnover. Our combined approach of proteomics, RNAseq and microarray analyses provides a comprehensive view of the molecular changes that accompany functional loss and alpha-synuclein pathology in Parkinson's disease, and may be instrumental to understand, diagnose and follow Parkinson's disease progression.

  12. Systems-Based Analyses of Brain Regions Functionally Impacted in Parkinson's Disease Reveals Underlying Causal Mechanisms

    PubMed Central

    Emig-Agius, Dorothea; Bessarabova, Marina; Ivliev, Alexander E.; Schüle, Birgit; Alexander, Jeff; Wallace, William; Halliday, Glenda M.; Langston, J. William; Braxton, Scott; Yednock, Ted; Shaler, Thomas; Johnston, Jennifer A.

    2014-01-01

    Detailed analysis of disease-affected tissue provides insight into molecular mechanisms contributing to pathogenesis. Substantia nigra, striatum, and cortex are functionally connected with increasing degrees of alpha-synuclein pathology in Parkinson's disease. We undertook functional and causal pathway analysis of gene expression and proteomic alterations in these three regions, and the data revealed pathways that correlated with disease progression. In addition, microarray and RNAseq experiments revealed previously unidentified causal changes related to oligodendrocyte function and synaptic vesicle release, and these and other changes were reflected across all brain regions. Importantly, subsets of these changes were replicated in Parkinson's disease blood; suggesting peripheral tissue may provide important avenues for understanding and measuring disease status and progression. Proteomic assessment revealed alterations in mitochondria and vesicular transport proteins that preceded gene expression changes indicating defects in translation and/or protein turnover. Our combined approach of proteomics, RNAseq and microarray analyses provides a comprehensive view of the molecular changes that accompany functional loss and alpha-synuclein pathology in Parkinson's disease, and may be instrumental to understand, diagnose and follow Parkinson's disease progression. PMID:25170892

  13. Language-specific phoneme representations revealed by electric and magnetic brain responses.

    PubMed

    Näätänen, R; Lehtokoski, A; Lennes, M; Cheour, M; Huotilainen, M; Iivonen, A; Vainio, M; Alku, P; Ilmoniemi, R J; Luuk, A; Allik, J; Sinkkonen, J; Alho, K

    1997-01-30

    There is considerable debate about whether the early processing of sounds depends on whether they form part of speech. Proponents of such speech specificity postulate the existence of language-dependent memory traces, which are activated in the processing of speech but not when equally complex, acoustic non-speech stimuli are processed. Here we report the existence of these traces in the human brain. We presented to Finnish subjects the Finnish phoneme prototype /e/ as the frequent stimulus, and other Finnish phoneme prototypes or a non-prototype (the Estonian prototype /õ/) as the infrequent stimulus. We found that the brain's automatic change-detection response, reflected electrically as the mismatch negativity (MMN), was enhanced when the infrequent, deviant stimulus was a prototype (the Finnish /ö/) relative to when it was a non-prototype (the Estonian /õ/). These phonemic traces, revealed by MMN, are language-specific, as /õ/ caused enhancement of MMN in Estonians. Whole-head magnetic recordings located the source of this native-language, phoneme-related response enhancement, and thus the language-specific memory traces, in the auditory cortex of the left hemisphere. PMID:9009189

  14. Diversity of sharp-wave–ripple LFP signatures reveals differentiated brain-wide dynamical events

    PubMed Central

    Ramirez-Villegas, Juan F.; Logothetis, Nikos K.; Besserve, Michel

    2015-01-01

    Sharp-wave–ripple (SPW-R) complexes are believed to mediate memory reactivation, transfer, and consolidation. However, their underlying neuronal dynamics at multiple scales remains poorly understood. Using concurrent hippocampal local field potential (LFP) recordings and functional MRI (fMRI), we study local changes in neuronal activity during SPW-R episodes and their brain-wide correlates. Analysis of the temporal alignment between SPW and ripple components reveals well-differentiated SPW-R subtypes in the CA1 LFP. SPW-R–triggered fMRI maps show that ripples aligned to the positive peak of their SPWs have enhanced neocortical metabolic up-regulation. In contrast, ripples occurring at the trough of their SPWs relate to weaker neocortical up-regulation and absent subcortical down-regulation, indicating differentiated involvement of neuromodulatory pathways in the ripple phenomenon mediated by long-range interactions. To our knowledge, this study provides the first evidence for the existence of SPW-R subtypes with differentiated CA1 activity and metabolic correlates in related brain areas, possibly serving different memory functions. PMID:26540729

  15. Diversity of sharp-wave-ripple LFP signatures reveals differentiated brain-wide dynamical events.

    PubMed

    Ramirez-Villegas, Juan F; Logothetis, Nikos K; Besserve, Michel

    2015-11-17

    Sharp-wave-ripple (SPW-R) complexes are believed to mediate memory reactivation, transfer, and consolidation. However, their underlying neuronal dynamics at multiple scales remains poorly understood. Using concurrent hippocampal local field potential (LFP) recordings and functional MRI (fMRI), we study local changes in neuronal activity during SPW-R episodes and their brain-wide correlates. Analysis of the temporal alignment between SPW and ripple components reveals well-differentiated SPW-R subtypes in the CA1 LFP. SPW-R-triggered fMRI maps show that ripples aligned to the positive peak of their SPWs have enhanced neocortical metabolic up-regulation. In contrast, ripples occurring at the trough of their SPWs relate to weaker neocortical up-regulation and absent subcortical down-regulation, indicating differentiated involvement of neuromodulatory pathways in the ripple phenomenon mediated by long-range interactions. To our knowledge, this study provides the first evidence for the existence of SPW-R subtypes with differentiated CA1 activity and metabolic correlates in related brain areas, possibly serving different memory functions. PMID:26540729

  16. Glycogen distribution in the microwave-fixed mouse brain reveals heterogeneous astrocytic patterns.

    PubMed

    Oe, Yuki; Baba, Otto; Ashida, Hitoshi; Nakamura, Kouichi C; Hirase, Hajime

    2016-09-01

    In the brain, glycogen metabolism has been implied in synaptic plasticity and learning, yet the distribution of this molecule has not been fully described. We investigated cerebral glycogen of the mouse by immunohistochemistry (IHC) using two monoclonal antibodies that have different affinities depending on the glycogen size. The use of focused microwave irradiation yielded well-defined glycogen immunoreactive signals compared with the conventional periodic acid-Schiff method. The IHC signals displayed a punctate distribution localized predominantly in astrocytic processes. Glycogen immunoreactivity (IR) was high in the hippocampus, striatum, cortex, and cerebellar molecular layer, whereas it was low in the white matter and most of the subcortical structures. Additionally, glycogen distribution in the hippocampal CA3-CA1 and striatum had a 'patchy' appearance with glycogen-rich and glycogen-poor astrocytes appearing in alternation. The glycogen patches were more evident with large-molecule glycogen in young adult mice but they were hardly observable in aged mice (1-2 years old). Our results reveal brain region-dependent glycogen accumulation and possibly metabolic heterogeneity of astrocytes. GLIA 2016;64:1532-1545. PMID:27353480

  17. The time course of word retrieval revealed by event-related brain potentials during overt speech

    PubMed Central

    Costa, Albert; Strijkers, Kristof; Martin, Clara; Thierry, Guillaume

    2009-01-01

    Speech production is one of the most fundamental activities of humans. A core cognitive operation involved in this skill is the retrieval of words from long-term memory, that is, from the mental lexicon. In this article, we establish the time course of lexical access by recording the brain electrical activity of participants while they named pictures aloud. By manipulating the ordinal position of pictures belonging to the same semantic categories, the cumulative semantic interference effect, we were able to measure the exact time at which lexical access takes place. We found significant correlations between naming latencies, ordinal position of pictures, and event-related potential mean amplitudes starting 200 ms after picture presentation and lasting for 180 ms. The study reveals that the brain engages extremely fast in the retrieval of words one wishes to utter and offers a clear time frame of how long it takes for the competitive process of activating and selecting words in the course of speech to be resolved. PMID:19934043

  18. Theory of mind for processing unexpected events across contexts.

    PubMed

    Dungan, James A; Stepanovic, Michael; Young, Liane

    2016-08-01

    Theory of mind, or mental state reasoning, may be particularly useful for making sense of unexpected events. Here, we investigated unexpected behavior across both social and non-social contexts in order to characterize the precise role of theory of mind in processing unexpected events. We used functional magnetic resonance imaging to examine how people respond to unexpected outcomes when initial expectations were based on (i) an object's prior behavior, (ii) an agent's prior behavior and (iii) an agent's mental states. Consistent with prior work, brain regions for theory of mind were preferentially recruited when people first formed expectations about social agents vs non-social objects. Critically, unexpected vs expected outcomes elicited greater activity in dorsomedial prefrontal cortex, which also discriminated in its spatial pattern of activity between unexpected and expected outcomes for social events. In contrast, social vs non-social events elicited greater activity in precuneus across both expected and unexpected outcomes. Finally, given prior information about an agent's behavior, unexpected vs expected outcomes elicited an especially robust response in right temporoparietal junction, and the magnitude of this difference across participants correlated negatively with autistic-like traits. Together, these findings illuminate the distinct contributions of brain regions for theory of mind for processing unexpected events across contexts. PMID:26969865

  19. Theory of mind for processing unexpected events across contexts.

    PubMed

    Dungan, James A; Stepanovic, Michael; Young, Liane

    2016-08-01

    Theory of mind, or mental state reasoning, may be particularly useful for making sense of unexpected events. Here, we investigated unexpected behavior across both social and non-social contexts in order to characterize the precise role of theory of mind in processing unexpected events. We used functional magnetic resonance imaging to examine how people respond to unexpected outcomes when initial expectations were based on (i) an object's prior behavior, (ii) an agent's prior behavior and (iii) an agent's mental states. Consistent with prior work, brain regions for theory of mind were preferentially recruited when people first formed expectations about social agents vs non-social objects. Critically, unexpected vs expected outcomes elicited greater activity in dorsomedial prefrontal cortex, which also discriminated in its spatial pattern of activity between unexpected and expected outcomes for social events. In contrast, social vs non-social events elicited greater activity in precuneus across both expected and unexpected outcomes. Finally, given prior information about an agent's behavior, unexpected vs expected outcomes elicited an especially robust response in right temporoparietal junction, and the magnitude of this difference across participants correlated negatively with autistic-like traits. Together, these findings illuminate the distinct contributions of brain regions for theory of mind for processing unexpected events across contexts.

  20. Brain

    MedlinePlus

    ... will return after updating. Resources Archived Modules Updates Brain Cerebrum The cerebrum is the part of the ... the outside of the brain and spinal cord. Brain Stem The brain stem is the part of ...

  1. Chromosome 15q11-13 duplication syndrome brain reveals epigenetic alterations in gene expression not predicted from copy number

    PubMed Central

    Hogart, Amber; Leung, Karen N.; Wang, Nicholas J.; Wu, David J.; Driscoll, Jennette; Vallero, Roxanne O.; Schanen, N. Carolyn

    2008-01-01

    Background Chromosome 15q11-13 contains a cluster of imprinted genes essential for normal mammalian neurodevelopment. Deficiencies in paternal or maternal 15q11-13 alleles result in Prader-Willi or Angelman syndromes, respectively, and maternal duplications lead to a distinct condition that often includes autism. Overexpression of maternally expressed imprinted genes is predicted to cause 15q11-13-associated autism, but a link between gene dosage and expression has not been experimentally determined in brain. Methods Post-mortem brain tissue was obtained from a male with 15q11-13 hexasomy and a female with 15q11-13 tetrasomy. Quantitative RT-PCR was used to measure ten 15q11-13 transcripts in maternal 15q11-13 duplication, Prader-Willi syndrome, and control brain samples. Southern blot, bisulfite sequencing and fluorescence in situ hybridization were used to investigate epigenetic mechanisms of gene regulation. Results Gene expression and DNA methylation correlated with parental gene dosage in the male 15q11-13 duplication sample with severe cognitive impairment and seizures. Strikingly, the female with autism and milder Prader-Willi-like characteristics demonstrated unexpected deficiencies in the paternally expressed transcripts SNRPN, NDN, HBII85, and HBII52 and unchanged levels of maternally expressed UBE3A compared to controls. Paternal expression abnormalities in the female duplication sample were consistent with elevated DNA methylation of the 15q11-13 imprinting control region (ICR). Expression of nonimprinted 15q11-13 GABA receptor subunit genes was significantly reduced specifically in the female 15q11-13 duplication brain without detectable GABRB3 methylation differences. Conclusion Our findings suggest that genetic copy number changes combined with additional genetic or environmental influences on epigenetic mechanisms impact outcome and clinical heterogeneity of 15q11-13 duplication syndromes. PMID:18835857

  2. Unexpected Angiography Findings and Effects on Management

    PubMed Central

    Neill, Matthew; Charles, Hearns W; Gross, Jonathan S; Farquharson, Sean; Deipolyi, Amy R

    2016-01-01

    Despite progress in noninvasive imaging with computed tomography and magnetic resonance imaging, conventional angiography still contributes to the diagnostic workup of oncologic and other diseases. Arteriography can reveal tumors not evident on cross-sectional imaging, in addition to defining aberrant or unexpected arterial supply to targeted lesions. This additional and potentially unanticipated information can alter management decisions during interventional procedures. PMID:27688932

  3. Unexpected Angiography Findings and Effects on Management.

    PubMed

    Neill, Matthew; Charles, Hearns W; Gross, Jonathan S; Farquharson, Sean; Deipolyi, Amy R

    2016-01-01

    Despite progress in noninvasive imaging with computed tomography and magnetic resonance imaging, conventional angiography still contributes to the diagnostic workup of oncologic and other diseases. Arteriography can reveal tumors not evident on cross-sectional imaging, in addition to defining aberrant or unexpected arterial supply to targeted lesions. This additional and potentially unanticipated information can alter management decisions during interventional procedures. PMID:27688932

  4. Unexpected Angiography Findings and Effects on Management

    PubMed Central

    Neill, Matthew; Charles, Hearns W; Gross, Jonathan S; Farquharson, Sean; Deipolyi, Amy R

    2016-01-01

    Despite progress in noninvasive imaging with computed tomography and magnetic resonance imaging, conventional angiography still contributes to the diagnostic workup of oncologic and other diseases. Arteriography can reveal tumors not evident on cross-sectional imaging, in addition to defining aberrant or unexpected arterial supply to targeted lesions. This additional and potentially unanticipated information can alter management decisions during interventional procedures.

  5. Brain Signals of Face Processing as Revealed by Event-Related Potentials

    PubMed Central

    Olivares, Ela I.; Iglesias, Jaime; Saavedra, Cristina; Trujillo-Barreto, Nelson J.; Valdés-Sosa, Mitchell

    2015-01-01

    We analyze the functional significance of different event-related potentials (ERPs) as electrophysiological indices of face perception and face recognition, according to cognitive and neurofunctional models of face processing. Initially, the processing of faces seems to be supported by early extrastriate occipital cortices and revealed by modulations of the occipital P1. This early response is thought to reflect the detection of certain primary structural aspects indicating the presence grosso modo of a face within the visual field. The posterior-temporal N170 is more sensitive to the detection of faces as complex-structured stimuli and, therefore, to the presence of its distinctive organizational characteristics prior to within-category identification. In turn, the relatively late and probably more rostrally generated N250r and N400-like responses might respectively indicate processes of access and retrieval of face-related information, which is stored in long-term memory (LTM). New methods of analysis of electrophysiological and neuroanatomical data, namely, dynamic causal modeling, single-trial and time-frequency analyses, are highly recommended to advance in the knowledge of those brain mechanisms concerning face processing. PMID:26160999

  6. Perceptual shift in bilingualism: brain potentials reveal plasticity in pre-attentive colour perception.

    PubMed

    Athanasopoulos, Panos; Dering, Benjamin; Wiggett, Alison; Kuipers, Jan-Rouke; Thierry, Guillaume

    2010-09-01

    The validity of the linguistic relativity principle continues to stimulate vigorous debate and research. The debate has recently shifted from the behavioural investigation arena to a more biologically grounded field, in which tangible physiological evidence for language effects on perception can be obtained. Using brain potentials in a colour oddball detection task with Greek and English speakers, a recent study suggests that language effects may exist at early stages of perceptual integration [Thierry, G., Athanasopoulos, P., Wiggett, A., Dering, B., & Kuipers, J. (2009). Unconscious effects of language-specific terminology on pre-attentive colour perception. Proceedings of the National Academy of Sciences, 106, 4567-4570]. In this paper, we test whether in Greek speakers exposure to a new cultural environment (UK) with contrasting colour terminology from their native language affects early perceptual processing as indexed by an electrophysiological correlate of visual detection of colour luminance. We also report semantic mapping of native colour terms and colour similarity judgements. Results reveal convergence of linguistic descriptions, cognitive processing, and early perception of colour in bilinguals. This result demonstrates for the first time substantial plasticity in early, pre-attentive colour perception and has important implications for the mechanisms that are involved in perceptual changes during the processes of language learning and acculturation.

  7. Interspecies avian brain chimeras reveal that large brain size differences are influenced by cell-interdependent processes.

    PubMed

    Chen, Chun-Chun; Balaban, Evan; Jarvis, Erich D

    2012-01-01

    Like humans, birds that exhibit vocal learning have relatively delayed telencephalon maturation, resulting in a disproportionately smaller brain prenatally but enlarged telencephalon in adulthood relative to vocal non-learning birds. To determine if this size difference results from evolutionary changes in cell-autonomous or cell-interdependent developmental processes, we transplanted telencephala from zebra finch donors (a vocal-learning species) into Japanese quail hosts (a vocal non-learning species) during the early neural tube stage (day 2 of incubation), and harvested the chimeras at later embryonic stages (between 9-12 days of incubation). The donor and host tissues fused well with each other, with known major fiber pathways connecting the zebra finch and quail parts of the brain. However, the overall sizes of chimeric finch telencephala were larger than non-transplanted finch telencephala at the same developmental stages, even though the proportional sizes of telencephalic subregions and fiber tracts were similar to normal finches. There were no significant changes in the size of chimeric quail host midbrains, even though they were innervated by the physically smaller zebra finch brain, including the smaller retinae of the finch eyes. Chimeric zebra finch telencephala had a decreased cell density relative to normal finches. However, cell nucleus size differences between each species were maintained as in normal birds. These results suggest that telencephalic size development is partially cell-interdependent, and that the mechanisms controlling the size of different brain regions may be functionally independent. PMID:22860132

  8. Interspecies Avian Brain Chimeras Reveal That Large Brain Size Differences Are Influenced by Cell–Interdependent Processes

    PubMed Central

    Chen, Chun-Chun; Balaban, Evan; Jarvis, Erich D.

    2012-01-01

    Like humans, birds that exhibit vocal learning have relatively delayed telencephalon maturation, resulting in a disproportionately smaller brain prenatally but enlarged telencephalon in adulthood relative to vocal non-learning birds. To determine if this size difference results from evolutionary changes in cell-autonomous or cell-interdependent developmental processes, we transplanted telencephala from zebra finch donors (a vocal-learning species) into Japanese quail hosts (a vocal non-learning species) during the early neural tube stage (day 2 of incubation), and harvested the chimeras at later embryonic stages (between 9–12 days of incubation). The donor and host tissues fused well with each other, with known major fiber pathways connecting the zebra finch and quail parts of the brain. However, the overall sizes of chimeric finch telencephala were larger than non-transplanted finch telencephala at the same developmental stages, even though the proportional sizes of telencephalic subregions and fiber tracts were similar to normal finches. There were no significant changes in the size of chimeric quail host midbrains, even though they were innervated by the physically smaller zebra finch brain, including the smaller retinae of the finch eyes. Chimeric zebra finch telencephala had a decreased cell density relative to normal finches. However, cell nucleus size differences between each species were maintained as in normal birds. These results suggest that telencephalic size development is partially cell-interdependent, and that the mechanisms controlling the size of different brain regions may be functionally independent. PMID:22860132

  9. Microfiberoptic fluorescence photobleaching reveals size-dependent macromolecule diffusion in extracellular space deep in brain.

    PubMed

    Zador, Zsolt; Magzoub, Mazin; Jin, Songwan; Manley, Geoffrey T; Papadopoulos, Marios C; Verkman, A S

    2008-03-01

    Diffusion in brain extracellular space (ECS) is important for nonsynaptic intercellular communication, extracellular ionic buffering, and delivery of drugs and metabolites. We measured macromolecular diffusion in normally light-inaccessible regions of mouse brain by microfiberoptic epifluorescence photobleaching, in which a fiberoptic with a micron-size tip is introduced deep in brain tissue. In brain cortex, the diffusion of a noninteracting molecule [fluorescein isothiocyanate (FITC)-dextran, 70 kDa] was slowed 4.5 +/- 0.5-fold compared with its diffusion in water (D(o)/D), and was depth-independent down to 800 microm from the brain surface. Diffusion was significantly accelerated (D(o)/D of 2.9+/-0.3) in mice lacking the glial water channel aquaporin-4. FITC-dextran diffusion varied greatly in different regions of brain, with D(o)/D of 3.5 +/- 0.3 in hippocampus and 7.4 +/- 0.3 in thalamus. Remarkably, D(o)/D in deep brain was strongly dependent on solute size, whereas diffusion in cortex changed little with solute size. Mathematical modeling of ECS diffusion required nonuniform ECS dimensions in deep brain, which we call "heterometricity," to account for the size-dependent diffusion. Our results provide the first data on molecular diffusion in ECS deep in brain in vivo and demonstrate previously unrecognized hindrance and heterometricity for diffusion of large macromolecules in deep brain.

  10. PCNA immunoreactivity revealing normal proliferative activity in the brain of an adult Elasmobranch, Torpedo marmorata.

    PubMed

    Margotta, Vito

    2007-01-01

    The brain of adult heterothermic vertebrates can be already provided of quiescent cells, scattered ("matrix cells") and/or clustered ("matrix areas"). These typical cells, in some regions located at or near ventricular surfaces and at peri-ependymal layers, in other territories populating their framework, maintain some embryonic properties and are responsible of normal or variously experimentally induced proliferative activities. On these topics there are a great number of reports concerning Teleostean Osteichthyes, Urodele and Anuran Amphibians, Lacertilian Reptiles. At the contrary, only few are the contributions regarding the Petromyzontidae. Involving an immunocytochemical marker, the Proliferating Cell Nuclear Antigen (PCNA), revealing proliferative events, in the last years we have undertaken a reappraisal focused on these encephalic performances in normal adult poikilothermal vertebrates. To provide a valid comparison between our results and the literature data, our choice of the specimens was based on the desire to employ organisms belonging to the same or phylogenetically close species used by previous Authors in similar studies. In our immunocytochemical panorama there is a substantial agreement between our contributions and bibliographic references concerning natural encephalic proliferative phenomena in these vertebrates. At this point of our study, the last missing piece was represented by the Chondrichthyes about which the literature data are lacking. In order to fill this gap, the aim of the present research is to investigate, involving the same PCNA test, whether proliferative events also persist in the brain of adult cartilaginous fishes. The immunostaining images obtained in the Elasmo branch Torpedo marmorata, well-known for the emission of high electrical discharges, exhibit undifferentiated cells in relationship with the ependymal epithelium lining the cavities of all cerebral districts; some other neuroblasts are scattered in the mesencephalic

  11. Brain network analysis reveals affected connectome structure in bipolar I disorder.

    PubMed

    Collin, Guusje; van den Heuvel, Martijn P; Abramovic, Lucija; Vreeker, Annabel; de Reus, Marcel A; van Haren, Neeltje E M; Boks, Marco P M; Ophoff, Roel A; Kahn, René S

    2016-01-01

    The notion that healthy brain function emerges from coordinated neural activity constrained by the brain's network of anatomical connections--i.e., the connectome--suggests that alterations in the connectome's wiring pattern may underlie brain disorders. Corroborating this hypothesis, studies in schizophrenia are indicative of altered connectome architecture including reduced communication efficiency, disruptions of central brain hubs, and affected "rich club" organization. Whether similar deficits are present in bipolar disorder is currently unknown. This study examines structural connectome topology in 216 bipolar I disorder patients as compared to 144 healthy controls, focusing in particular on central regions (i.e., brain hubs) and connections (i.e., rich club connections, interhemispheric connections) of the brain's network. We find that bipolar I disorder patients exhibit reduced global efficiency (-4.4%, P =0.002) and that this deficit relates (r = 0.56, P < 0.001) to reduced connectivity strength of interhemispheric connections (-13.0%, P = 0.001). Bipolar disorder patients were found not to show predominant alterations in the strength of brain hub connections in general, or of connections spanning brain hubs (i.e., "rich club" connections) in particular (all P > 0.1). These findings highlight a role for aberrant brain network architecture in bipolar I disorder with reduced global efficiency in association with disruptions in interhemispheric connectivity, while the central "rich club" system appears not to be particularly affected.

  12. Fossil skulls reveal that blood flow rate to the brain increased faster than brain volume during human evolution

    NASA Astrophysics Data System (ADS)

    Seymour, Roger S.; Bosiocic, Vanya; Snelling, Edward P.

    2016-08-01

    The evolution of human cognition has been inferred from anthropological discoveries and estimates of brain size from fossil skulls. A more direct measure of cognition would be cerebral metabolic rate, which is proportional to cerebral blood flow rate (perfusion). The hominin cerebrum is supplied almost exclusively by the internal carotid arteries. The sizes of the foramina that transmitted these vessels in life can be measured in hominin fossil skulls and used to calculate cerebral perfusion rate. Perfusion in 11 species of hominin ancestors, from Australopithecus to archaic Homo sapiens, increases disproportionately when scaled against brain volume (the allometric exponent is 1.41). The high exponent indicates an increase in the metabolic intensity of cerebral tissue in later Homo species, rather than remaining constant (1.0) as expected by a linear increase in neuron number, or decreasing according to Kleiber's Law (0.75). During 3 Myr of hominin evolution, cerebral tissue perfusion increased 1.7-fold, which, when multiplied by a 3.5-fold increase in brain size, indicates a 6.0-fold increase in total cerebral blood flow rate. This is probably associated with increased interneuron connectivity, synaptic activity and cognitive function, which all ultimately depend on cerebral metabolic rate.

  13. Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets

    PubMed Central

    Santagata, Sandro; Cahill, Daniel P.; Taylor-Weiner, Amaro; Jones, Robert T.; Van Allen, Eliezer M.; Lawrence, Michael S.; Horowitz, Peleg M.; Cibulskis, Kristian; Ligon, Keith L.; Tabernero, Josep; Seoane, Joan; Martinez-Saez, Elena; Curry, William T.; Dunn, Ian F.; Paek, Sun Ha; Park, Sung-Hye; McKenna, Aaron; Chevalier, Aaron; Rosenberg, Mara; Barker, Frederick G.; Gill, Corey M.; Van Hummelen, Paul; Thorner, Aaron R.; Johnson, Bruce E.; Hoang, Mai P.; Choueiri, Toni K.; Signoretti, Sabina; Sougnez, Carrie; Rabin, Michael S.; Lin, Nancy U.; Winer, Eric P.; Stemmer-Rachamimov, Anat; Meyerson, Matthew; Garraway, Levi; Gabriel, Stacey; Lander, Eric S.; Beroukhim, Rameen; Batchelor, Tracy T.; Baselga, Jose; Louis, David N.

    2016-01-01

    Brain metastases are associated with a dismal prognosis. Whether brain metastases harbor distinct genetic alterations beyond those observed in primary tumors is unknown. We performed whole-exome sequencing of 86 matched brain metastases, primary tumors and normal tissue. In all clonally related cancer samples, we observed branched evolution, where all metastatic and primary sites shared a common ancestor yet continued to evolve independently. In 53% of cases, we found potentially clinically informative alterations in the brain metastases not detected in the matched primary-tumor sample. In contrast, spatially and temporally separated brain metastasis sites were genetically homogenous. Distal extracranial and regional lymph node metastases were highly divergent from brain metastases. We detected alterations associated with sensitivity to PI3K/AKT/mTOR, CDK, and HER2/EGFR inhibitors in the brain metastases. Genomic analysis of brain metastases provides an opportunity to identify potentially clinically informative alterations not detected in clinically sampled primary tumors, regional lymph nodes, or extracranial metastases. PMID:26410082

  14. Graph Theoretical Analysis Reveals: Women's Brains Are Better Connected than Men's.

    PubMed

    Szalkai, Balázs; Varga, Bálint; Grolmusz, Vince

    2015-01-01

    Deep graph-theoretic ideas in the context with the graph of the World Wide Web led to the definition of Google's PageRank and the subsequent rise of the most popular search engine to date. Brain graphs, or connectomes, are being widely explored today. We believe that non-trivial graph theoretic concepts, similarly as it happened in the case of the World Wide Web, will lead to discoveries enlightening the structural and also the functional details of the animal and human brains. When scientists examine large networks of tens or hundreds of millions of vertices, only fast algorithms can be applied because of the size constraints. In the case of diffusion MRI-based structural human brain imaging, the effective vertex number of the connectomes, or brain graphs derived from the data is on the scale of several hundred today. That size facilitates applying strict mathematical graph algorithms even for some hard-to-compute (or NP-hard) quantities like vertex cover or balanced minimum cut. In the present work we have examined brain graphs, computed from the data of the Human Connectome Project, recorded from male and female subjects between ages 22 and 35. Significant differences were found between the male and female structural brain graphs: we show that the average female connectome has more edges, is a better expander graph, has larger minimal bisection width, and has more spanning trees than the average male connectome. Since the average female brain weighs less than the brain of males, these properties show that the female brain has better graph theoretical properties, in a sense, than the brain of males. It is known that the female brain has a smaller gray matter/white matter ratio than males, that is, a larger white matter/gray matter ratio than the brain of males; this observation is in line with our findings concerning the number of edges, since the white matter consists of myelinated axons, which, in turn, roughly correspond to the connections in the brain graph

  15. Graph Theoretical Analysis Reveals: Women’s Brains Are Better Connected than Men’s

    PubMed Central

    Szalkai, Balázs; Varga, Bálint; Grolmusz, Vince

    2015-01-01

    Deep graph-theoretic ideas in the context with the graph of the World Wide Web led to the definition of Google’s PageRank and the subsequent rise of the most popular search engine to date. Brain graphs, or connectomes, are being widely explored today. We believe that non-trivial graph theoretic concepts, similarly as it happened in the case of the World Wide Web, will lead to discoveries enlightening the structural and also the functional details of the animal and human brains. When scientists examine large networks of tens or hundreds of millions of vertices, only fast algorithms can be applied because of the size constraints. In the case of diffusion MRI-based structural human brain imaging, the effective vertex number of the connectomes, or brain graphs derived from the data is on the scale of several hundred today. That size facilitates applying strict mathematical graph algorithms even for some hard-to-compute (or NP-hard) quantities like vertex cover or balanced minimum cut. In the present work we have examined brain graphs, computed from the data of the Human Connectome Project, recorded from male and female subjects between ages 22 and 35. Significant differences were found between the male and female structural brain graphs: we show that the average female connectome has more edges, is a better expander graph, has larger minimal bisection width, and has more spanning trees than the average male connectome. Since the average female brain weighs less than the brain of males, these properties show that the female brain has better graph theoretical properties, in a sense, than the brain of males. It is known that the female brain has a smaller gray matter/white matter ratio than males, that is, a larger white matter/gray matter ratio than the brain of males; this observation is in line with our findings concerning the number of edges, since the white matter consists of myelinated axons, which, in turn, roughly correspond to the connections in the brain graph

  16. Brain classification reveals the right cerebellum as the best biomarker of dyslexia

    PubMed Central

    Pernet, Cyril R; Poline, Jean Baptiste; Demonet, Jean François; Rousselet, Guillaume A

    2009-01-01

    Background Developmental dyslexia is a specific cognitive disorder in reading acquisition that has genetic and neurological origins. Despite histological evidence for brain differences in dyslexia, we recently demonstrated that in large cohort of subjects, no differences between control and dyslexic readers can be found at the macroscopic level (MRI voxel), because of large variances in brain local volumes. In the present study, we aimed at finding brain areas that most discriminate dyslexic from control normal readers despite the large variance across subjects. After segmenting brain grey matter, normalizing brain size and shape and modulating the voxels' content, normal readers' brains were used to build a 'typical' brain via bootstrapped confidence intervals. Each dyslexic reader's brain was then classified independently at each voxel as being within or outside the normal range. We used this simple strategy to build a brain map showing regional percentages of differences between groups. The significance of this map was then assessed using a randomization technique. Results The right cerebellar declive and the right lentiform nucleus were the two areas that significantly differed the most between groups with 100% of the dyslexic subjects (N = 38) falling outside of the control group (N = 39) 95% confidence interval boundaries. The clinical relevance of this result was assessed by inquiring cognitive brain-based differences among dyslexic brain subgroups in comparison to normal readers' performances. The strongest difference between dyslexic subgroups was observed between subjects with lower cerebellar declive (LCD) grey matter volumes than controls and subjects with higher cerebellar declive (HCD) grey matter volumes than controls. Dyslexic subjects with LCD volumes performed worse than subjects with HCD volumes in phonologically and lexicon related tasks. Furthermore, cerebellar and lentiform grey matter volumes interacted in dyslexic subjects, so that lower and

  17. Exploratory Metabolomic Analyses Reveal Compounds Correlated with Lutein Concentration in Frontal Cortex, Hippocampus, and Occipital Cortex of Human Infant Brain.

    PubMed

    Lieblein-Boff, Jacqueline C; Johnson, Elizabeth J; Kennedy, Adam D; Lai, Chron-Si; Kuchan, Matthew J

    2015-01-01

    Lutein is a dietary carotenoid well known for its role as an antioxidant in the macula, and recent reports implicate a role for lutein in cognitive function. Lutein is the dominant carotenoid in both pediatric and geriatric brain tissue. In addition, cognitive function in older adults correlated with macular and postmortem brain lutein concentrations. Furthermore, lutein was found to preferentially accumulate in the infant brain in comparison to other carotenoids that are predominant in diet. While lutein is consistently related to cognitive function, the mechanisms by which lutein may influence cognition are not clear. In an effort to identify potential mechanisms through which lutein might influence neurodevelopment, an exploratory study relating metabolite signatures and lutein was completed. Post-mortem metabolomic analyses were performed on human infant brain tissues in three regions important for learning and memory: the frontal cortex, hippocampus, and occipital cortex. Metabolomic profiles were compared to lutein concentration, and correlations were identified and reported here. A total of 1276 correlations were carried out across all brain regions. Of 427 metabolites analyzed, 257 were metabolites of known identity. Unidentified metabolite correlations (510) were excluded. In addition, moderate correlations with xenobiotic relationships (2) or those driven by single outliers (3) were excluded from further study. Lutein concentrations correlated with lipid pathway metabolites, energy pathway metabolites, brain osmolytes, amino acid neurotransmitters, and the antioxidant homocarnosine. These correlations were often brain region-specific. Revealing relationships between lutein and metabolic pathways may help identify potential candidates on which to complete further analyses and may shed light on important roles of lutein in the human brain during development.

  18. Exploratory Metabolomic Analyses Reveal Compounds Correlated with Lutein Concentration in Frontal Cortex, Hippocampus, and Occipital Cortex of Human Infant Brain

    PubMed Central

    Lieblein-Boff, Jacqueline C.; Johnson, Elizabeth J.; Kennedy, Adam D.; Lai, Chron-Si; Kuchan, Matthew J.

    2015-01-01

    Lutein is a dietary carotenoid well known for its role as an antioxidant in the macula, and recent reports implicate a role for lutein in cognitive function. Lutein is the dominant carotenoid in both pediatric and geriatric brain tissue. In addition, cognitive function in older adults correlated with macular and postmortem brain lutein concentrations. Furthermore, lutein was found to preferentially accumulate in the infant brain in comparison to other carotenoids that are predominant in diet. While lutein is consistently related to cognitive function, the mechanisms by which lutein may influence cognition are not clear. In an effort to identify potential mechanisms through which lutein might influence neurodevelopment, an exploratory study relating metabolite signatures and lutein was completed. Post-mortem metabolomic analyses were performed on human infant brain tissues in three regions important for learning and memory: the frontal cortex, hippocampus, and occipital cortex. Metabolomic profiles were compared to lutein concentration, and correlations were identified and reported here. A total of 1276 correlations were carried out across all brain regions. Of 427 metabolites analyzed, 257 were metabolites of known identity. Unidentified metabolite correlations (510) were excluded. In addition, moderate correlations with xenobiotic relationships (2) or those driven by single outliers (3) were excluded from further study. Lutein concentrations correlated with lipid pathway metabolites, energy pathway metabolites, brain osmolytes, amino acid neurotransmitters, and the antioxidant homocarnosine. These correlations were often brain region—specific. Revealing relationships between lutein and metabolic pathways may help identify potential candidates on which to complete further analyses and may shed light on important roles of lutein in the human brain during development. PMID:26317757

  19. Chronic lead and brain development: intraocular brain grafts as a method to reveal regional and temporal effects in the central nervous system

    SciTech Connect

    Bjoerklund, H.; Olson, L.; Seiger, A.; Hoffer, B.

    1980-06-01

    A model is presented for selective studies of regional and temporal effects of chronic lead exposure on brain development, based on intraocular brain tissue grafting. Adult rat recipients were given lead acetate (1 to 2%) in their drinking water. Controls received sodium acetate in the drinking water or tap water. One week later, developing brain tissues obtained prenatally from different regions of the central nervous system were homologously grafted to the anterior chamber of the eye. Survival, vascularization, and growth were followed in oculo by repeated measurements of graft size. Growth curves were thus obtained for grafts from isolated selected brain areas, grafted at different stages of development to recipients on different concentrations of lead. Lead treatment (1%) caused a significant and pronounced delay of growth of the substantia nigra area during the second and third week postgrafting, approximately corresponding to the first 2 weeks after birth. Grafts of the hippocampal formation showed a slight impairment of growth following lead treatment while there were no detectable effects on size of cerebellar grafts. Grafts of the developing parietal cerebral cortex were inhibited in their growth in host animals given 2% lead while there was a small but significant increase in size following 1% lead. These results demonstrate the applicability of the grafting technique for studies of chronic low level lead intoxication. The method has revealed highly significant effects of lead on growth of certain selected brain areas and will be used for further histological, biochemical, and electrophysiological analysis of chronic lead effects on development of defined brain areas.

  20. DNA microarray analysis of functionally discrete human brain regions reveals divergent transcriptional profiles

    PubMed Central

    Evans, S.J.; Choudary, P.V.; Vawter, M.P.; Li, J.; Meador-Woodruff, J.H.; Lopez, J.F.; Burke, S.M.; Thompson, R.C.; Myers, R.M.; Jones, E.G.; Bunney, W.E.; Watson, S.J.; Akil, H.

    2010-01-01

    Transcriptional profiles within discrete human brain regions are likely to reflect structural and functional specialization. Using DNA microarray technology, this study investigates differences in transcriptional profiles of highly divergent brain regions (the cerebellar cortex and the cerebral cortex) as well as differences between two closely related brain structures (the anterior cingulate cortex and the dorsolateral prefrontal cortex). Replication of this study across three independent laboratories, to address false-positive and false-negative results using microarray technology, is also discussed. We find greater than a thousand transcripts to be differentially expressed between cerebellum and cerebral cortex and very few transcripts to be differentially expressed between the two neocortical regions. We further characterized transcripts that were found to be specifically expressed within brain regions being compared and found that ontological classes representing signal transduction machinery, neurogenesis, synaptic transmission, and transcription factors were most highly represented. PMID:14572446

  1. Metabolite mapping reveals severe widespread perturbation of multiple metabolic processes in Huntington's disease human brain.

    PubMed

    Patassini, Stefano; Begley, Paul; Xu, Jingshu; Church, Stephanie J; Reid, Suzanne J; Kim, Eric H; Curtis, Maurice A; Dragunow, Mike; Waldvogel, Henry J; Snell, Russell G; Unwin, Richard D; Faull, Richard L M; Cooper, Garth J S

    2016-09-01

    Huntington's disease (HD) is a genetically-mediated neurodegenerative disorder wherein the aetiological defect is a mutation in the Huntington's gene (HTT), which alters the structure of the huntingtin protein (Htt) through lengthening of its polyglutamine tract, thus initiating a cascade that ultimately leads to premature death. However, neurodegeneration typically manifests in HD only in middle age, and mechanisms linking the causative mutation to brain disease are poorly understood. Brain metabolism is severely perturbed in HD, and some studies have indicated a potential role for mutant Htt as a driver of these metabolic aberrations. Here, our objective was to determine the effects of HD on brain metabolism by measuring levels of polar metabolites in regions known to undergo varying degrees of damage. We performed gas-chromatography/mass spectrometry-based metabolomic analyses in a case-control study of eleven brain regions in short post-mortem-delay human tissue from nine well-characterized HD patients and nine matched controls. In each patient, we measured metabolite content in representative tissue-samples from eleven brain regions that display varying degrees of damage in HD, thus identifying the presence and abundance of 63 different metabolites from several molecular classes, including carbohydrates, amino acids, nucleosides, and neurotransmitters. Robust alterations in regional brain-metabolite abundances were observed in HD patients: these included changes in levels of small molecules that play important roles as intermediates in the tricarboxylic-acid and urea cycles, and amino-acid metabolism. Our findings point to widespread disruption of brain metabolism and indicate a complex phenotype beyond the gradient of neuropathologic damage observed in HD brain. PMID:27267344

  2. Positron Emission Tomography Reveals Abnormal Topological Organization in Functional Brain Network in Diabetic Patients

    PubMed Central

    Qiu, Xiangzhe; Zhang, Yanjun; Feng, Hongbo; Jiang, Donglang

    2016-01-01

    Recent studies have demonstrated alterations in the topological organization of structural brain networks in diabetes mellitus (DM). However, the DM-related changes in the topological properties in functional brain networks are unexplored so far. We therefore used fluoro-D-glucose positron emission tomography (FDG-PET) data to construct functional brain networks of 73 DM patients and 91 sex- and age-matched normal controls (NCs), followed by a graph theoretical analysis. We found that both DM patients and NCs had a small-world topology in functional brain network. In comparison to the NC group, the DM group was found to have significantly lower small-world index, lower normalized clustering coefficients and higher normalized characteristic path length. Moreover, for diabetic patients, the nodal centrality was significantly reduced in the right rectus, the right cuneus, the left middle occipital gyrus, and the left postcentral gyrus, and it was significantly increased in the orbitofrontal region of the left middle frontal gyrus, the left olfactory region, and the right paracentral lobule. Our results demonstrated that the diabetic brain was associated with disrupted topological organization in the functional PET network, thus providing functional evidence for the abnormalities of brain networks in DM. PMID:27303259

  3. Delay-correlation landscape reveals characteristic time delays of brain rhythms and heart interactions

    NASA Astrophysics Data System (ADS)

    Lin, Aijing; Liu, Kang K. L.; Bartsch, Ronny P.; Ivanov, Plamen Ch.

    2016-05-01

    Within the framework of `Network Physiology', we ask a fundamental question of how modulations in cardiac dynamics emerge from networked brain-heart interactions. We propose a generalized time-delay approach to identify and quantify dynamical interactions between physiologically relevant brain rhythms and the heart rate. We perform empirical analysis of synchronized continuous EEG and ECG recordings from 34 healthy subjects during night-time sleep. For each pair of brain rhythm and heart interaction, we construct a delay-correlation landscape (DCL) that characterizes how individual brain rhythms are coupled to the heart rate, and how modulations in brain and cardiac dynamics are coordinated in time. We uncover characteristic time delays and an ensemble of specific profiles for the probability distribution of time delays that underly brain-heart interactions. These profiles are consistently observed in all subjects, indicating a universal pattern. Tracking the evolution of DCL across different sleep stages, we find that the ensemble of time-delay profiles changes from one physiologic state to another, indicating a strong association with physiologic state and function. The reported observations provide new insights on neurophysiological regulation of cardiac dynamics, with potential for broad clinical applications. The presented approach allows one to simultaneously capture key elements of dynamic interactions, including characteristic time delays and their time evolution, and can be applied to a range of coupled dynamical systems.

  4. What have novel imaging techniques revealed about metabolism in the aging brain?

    PubMed

    Lin, Ai-Ling; Rothman, Douglas L

    2014-05-01

    Brain metabolism declines with age and do so in an accelerated manner in neurodegenerative disorders. Noninvasive neuroimaging techniques have played an important role to identify the metabolic biomarkers in aging brain. Particularly, PET with fluorine-18 ((18)F)-labeled 2-fluoro-2-deoxy-d-glucose tracer and proton magnetic resonance spectroscopy (MRS) have been widely used to monitor changes in brain metabolism over time, identify the risk for Alzheimer's disease (AD) and predict the conversion from mild cognitive impairment to AD. Novel techniques, including PET carbon-11 Pittsburgh compound B, carbon-13 and phosphorus-31 MRS, have also been introduced to determine Aβ plaques deposition, mitochondrial functions and brain bioenergetics in aging brain and neurodegenerative disorders. Here, we introduce the basic principle of the imaging techniques, review the findings from 2-fluoro-2-deoxy-d-glucose-PET, Pittsburgh compound B PET, proton, carbon-13 and phosphorus-31 MRS on changes in metabolism in normal aging brain, mild cognitive impairment and AD, and discuss the potential of neuroimaging to identify effective interventions and treatment efficacy for neurodegenerative disorders.

  5. Intrinsic connectivity in the human brain does not reveal networks for 'basic' emotions.

    PubMed

    Touroutoglou, Alexandra; Lindquist, Kristen A; Dickerson, Bradford C; Barrett, Lisa Feldman

    2015-09-01

    We tested two competing models for the brain basis of emotion, the basic emotion theory and the conceptual act theory of emotion, using resting-state functional connectivity magnetic resonance imaging (rs-fcMRI). The basic emotion view hypothesizes that anger, sadness, fear, disgust and happiness each arise from a brain network that is innate, anatomically constrained and homologous in other animals. The conceptual act theory of emotion hypothesizes that an instance of emotion is a brain state constructed from the interaction of domain-general, core systems within the brain such as the salience, default mode and frontoparietal control networks. Using peak coordinates derived from a meta-analysis of task-evoked emotion fMRI studies, we generated a set of whole-brain rs-fcMRI 'discovery' maps for each emotion category and examined the spatial overlap in their conjunctions. Instead of discovering a specific network for each emotion category, variance in the discovery maps was accounted for by the known domain-general network. Furthermore, the salience network is observed as part of every emotion category. These results indicate that specific networks for each emotion do not exist within the intrinsic architecture of the human brain and instead support the conceptual act theory of emotion.

  6. Delay-correlation landscape reveals characteristic time delays of brain rhythms and heart interactions.

    PubMed

    Lin, Aijing; Liu, Kang K L; Bartsch, Ronny P; Ivanov, Plamen Ch

    2016-05-13

    Within the framework of 'Network Physiology', we ask a fundamental question of how modulations in cardiac dynamics emerge from networked brain-heart interactions. We propose a generalized time-delay approach to identify and quantify dynamical interactions between physiologically relevant brain rhythms and the heart rate. We perform empirical analysis of synchronized continuous EEG and ECG recordings from 34 healthy subjects during night-time sleep. For each pair of brain rhythm and heart interaction, we construct a delay-correlation landscape (DCL) that characterizes how individual brain rhythms are coupled to the heart rate, and how modulations in brain and cardiac dynamics are coordinated in time. We uncover characteristic time delays and an ensemble of specific profiles for the probability distribution of time delays that underly brain-heart interactions. These profiles are consistently observed in all subjects, indicating a universal pattern. Tracking the evolution of DCL across different sleep stages, we find that the ensemble of time-delay profiles changes from one physiologic state to another, indicating a strong association with physiologic state and function. The reported observations provide new insights on neurophysiological regulation of cardiac dynamics, with potential for broad clinical applications. The presented approach allows one to simultaneously capture key elements of dynamic interactions, including characteristic time delays and their time evolution, and can be applied to a range of coupled dynamical systems. PMID:27044991

  7. Surface area and cortical thickness descriptors reveal different attributes of the structural human brain networks.

    PubMed

    Sanabria-Diaz, Gretel; Melie-García, Lester; Iturria-Medina, Yasser; Alemán-Gómez, Yasser; Hernández-González, Gertrudis; Valdés-Urrutia, Lourdes; Galán, Lídice; Valdés-Sosa, Pedro

    2010-05-01

    Recently, a related morphometry-based connection concept has been introduced using local mean cortical thickness and volume to study the underlying complex architecture of the brain networks. In this article, the surface area is employed as a morphometric descriptor to study the concurrent changes between brain structures and to build binarized connectivity graphs. The statistical similarity in surface area between pair of regions was measured by computing the partial correlation coefficient across 186 normal subjects of the Cuban Human Brain Mapping Project. We demonstrated that connectivity matrices obtained follow a small-world behavior for two different parcellations of the brain gray matter. The properties of the connectivity matrices were compared to the matrices obtained using the mean cortical thickness for the same cortical parcellations. The topology of the cortical thickness and surface area networks were statistically different, demonstrating that both capture distinct properties of the interaction or different aspects of the same interaction (mechanical, anatomical, chemical, etc.) between brain structures. This finding could be explained by the fact that each descriptor is driven by distinct cellular mechanisms as result of a distinct genetic origin. To our knowledge, this is the first time that surface area is used to study the morphological connectivity of brain networks. PMID:20083210

  8. Functional brain imaging in 14 patients with dissociative amnesia reveals right inferolateral prefrontal hypometabolism.

    PubMed

    Brand, Matthias; Eggers, Carsten; Reinhold, Nadine; Fujiwara, Esther; Kessler, Josef; Heiss, Wolf-Dieter; Markowitsch, Hans J

    2009-10-30

    Dissociative amnesia is a condition usually characterized by severely impaired retrograde memory functioning in the absence of structural brain damage. Recent case studies nevertheless found functional brain changes in patients suffering from autobiographical-episodic memory loss in the cause of dissociative amnesia. Functional changes were demonstrated in both resting state and memory retrieval conditions. In addition, some but not all cases also showed other neuropsychological impairments beyond retrograde memory deficits. However, there is no group study available that examined potential functional brain abnormalities and accompanying neuropsychological deteriorations in larger samples of patients with dissociative retrograde amnesia. We report functional imaging and neuropsychological data acquired in 14 patients with dissociative amnesia following stressful or traumatic events. All patients suffered from autobiographical memory loss. In addition, approximately half of the patients had deficits in anterograde memory and executive functioning. Accompanying functional brain changes were measured by [18F]fluorodeoxyglucose positron emission tomography (FDG-PET). Regional glucose utilization of the patients was compared with that of 19 healthy subjects, matched for age and gender. We found significantly decreased glucose utilization in the right inferolateral prefrontal cortex in the patients. Hypometabolism in this brain region, known to be involved in retrieval of autobiographical memories and self-referential processing, may be a functional brain correlate of dissociative amnesia.

  9. Delay-correlation landscape reveals characteristic time delays of brain rhythms and heart interactions.

    PubMed

    Lin, Aijing; Liu, Kang K L; Bartsch, Ronny P; Ivanov, Plamen Ch

    2016-05-13

    Within the framework of 'Network Physiology', we ask a fundamental question of how modulations in cardiac dynamics emerge from networked brain-heart interactions. We propose a generalized time-delay approach to identify and quantify dynamical interactions between physiologically relevant brain rhythms and the heart rate. We perform empirical analysis of synchronized continuous EEG and ECG recordings from 34 healthy subjects during night-time sleep. For each pair of brain rhythm and heart interaction, we construct a delay-correlation landscape (DCL) that characterizes how individual brain rhythms are coupled to the heart rate, and how modulations in brain and cardiac dynamics are coordinated in time. We uncover characteristic time delays and an ensemble of specific profiles for the probability distribution of time delays that underly brain-heart interactions. These profiles are consistently observed in all subjects, indicating a universal pattern. Tracking the evolution of DCL across different sleep stages, we find that the ensemble of time-delay profiles changes from one physiologic state to another, indicating a strong association with physiologic state and function. The reported observations provide new insights on neurophysiological regulation of cardiac dynamics, with potential for broad clinical applications. The presented approach allows one to simultaneously capture key elements of dynamic interactions, including characteristic time delays and their time evolution, and can be applied to a range of coupled dynamical systems.

  10. Positron Emission Tomography Reveals Abnormal Topological Organization in Functional Brain Network in Diabetic Patients.

    PubMed

    Qiu, Xiangzhe; Zhang, Yanjun; Feng, Hongbo; Jiang, Donglang

    2016-01-01

    Recent studies have demonstrated alterations in the topological organization of structural brain networks in diabetes mellitus (DM). However, the DM-related changes in the topological properties in functional brain networks are unexplored so far. We therefore used fluoro-D-glucose positron emission tomography (FDG-PET) data to construct functional brain networks of 73 DM patients and 91 sex- and age-matched normal controls (NCs), followed by a graph theoretical analysis. We found that both DM patients and NCs had a small-world topology in functional brain network. In comparison to the NC group, the DM group was found to have significantly lower small-world index, lower normalized clustering coefficients and higher normalized characteristic path length. Moreover, for diabetic patients, the nodal centrality was significantly reduced in the right rectus, the right cuneus, the left middle occipital gyrus, and the left postcentral gyrus, and it was significantly increased in the orbitofrontal region of the left middle frontal gyrus, the left olfactory region, and the right paracentral lobule. Our results demonstrated that the diabetic brain was associated with disrupted topological organization in the functional PET network, thus providing functional evidence for the abnormalities of brain networks in DM. PMID:27303259

  11. Do salt cravings in children with autistic disorders reveal low blood sodium depleting brain taurine and glutamine?

    PubMed

    Good, Peter

    2011-12-01

    Because boys are four times more likely than girls to develop autism, the role of male hormones (androgens) has received considerable scrutiny. Some researchers implicate arginine vasopressin, an androgen-dependent hormone from the pituitary gland that elicits male behavior. Elevated vasopressin is also the most common cause of low blood sodium (hyponatremia)--most serious in the brains of children. Hyponatremia causes astrocytes to swell, then release the amino acids taurine and glutamine and their water to compensate. Taurin--the brain osmolyte/inhibitory neurotransmitter that suppresses vasopressin--was the amino acid most wasted or depleted in urine of autistic children. Glutamine is a critical metabolic fuel in brain neurons, astrocytes, endothelial cells, and the intestines, especially during hypoglycemia. Because glutamine is not thought to cross the blood-brain barrier significantly, the implications of low blood glutamine in these children are not recognized. Yet children with high brain glutamine from urea cycle disorders are rarely diagnosed with autistic disorders. Other common events in autistic children that release vasopressin are gastrointestinal inflammation, hypoglycemia, and stress. Signs of hyponatremia in these children are salt cravings reported online and anecdotally, deep yellow urine revealing concentration, and relief of autistic behavior by fluid/salt diets. Several interventions offer promise: (a) taurine to suppress vasopressin and replenish astrocytes; (b) glutamine as fuel for intestines and brain; (c) arginine to spare glutamine, detoxify ammonia, and increase brain blood flow; and (d) oral rehydration salts to compensate dilutional hyponatremia. This hypothesis appears eminently testable: Does your child crave salt? Is his urine deep yellow?

  12. In vivo NAD assay reveals the intracellular NAD contents and redox state in healthy human brain and their age dependences.

    PubMed

    Zhu, Xiao-Hong; Lu, Ming; Lee, Byeong-Yeul; Ugurbil, Kamil; Chen, Wei

    2015-03-01

    NAD is an essential metabolite that exists in NAD(+) or NADH form in all living cells. Despite its critical roles in regulating mitochondrial energy production through the NAD(+)/NADH redox state and modulating cellular signaling processes through the activity of the NAD(+)-dependent enzymes, the method for quantifying intracellular NAD contents and redox state is limited to a few in vitro or ex vivo assays, which are not suitable for studying a living brain or organ. Here, we present a magnetic resonance (MR) -based in vivo NAD assay that uses the high-field MR scanner and is capable of noninvasively assessing NAD(+) and NADH contents and the NAD(+)/NADH redox state in intact human brain. The results of this study provide the first insight, to our knowledge, into the cellular NAD concentrations and redox state in the brains of healthy volunteers. Furthermore, an age-dependent increase of intracellular NADH and age-dependent reductions in NAD(+), total NAD contents, and NAD(+)/NADH redox potential of the healthy human brain were revealed in this study. The overall findings not only provide direct evidence of declined mitochondrial functions and altered NAD homeostasis that accompany the normal aging process but also, elucidate the merits and potentials of this new NAD assay for noninvasively studying the intracellular NAD metabolism and redox state in normal and diseased human brain or other organs in situ.

  13. An unexpected tetanus case.

    PubMed

    Ergonul, Onder; Egeli, Demet; Kahyaoglu, Bulent; Bahar, Mois; Etienne, Mill; Bleck, Thomas

    2016-06-01

    1 million cases of tetanus are estimated to occur worldwide each year, with more than 200 000 deaths. Tetanus is a life-threatening but preventable disease caused by a toxin produced by Clostridium tetani-a Gram-positive bacillus found in high concentrations in soil and animal excrement. Tetanus is almost completely preventable by active immunisation, but very rarely unexpected cases can occur in individuals who have been previously vaccinated. We report a case of generalised tetanus in a 22-year-old woman that arose despite the protective antitoxin antibody in her serum. The patient received all her vaccinations in the USA; her last vaccination was 6 years ago. The case was unusual because the patient had received all standard vaccinations, had no defined port of entry at disease onset, and had symptoms lasting for 6 months. Tetanus can present with unusual clinical forms; therefore, the diagnosis and management of this rare but difficult disease should be updated. In this Grand Round, we review the clinical features, epidemiology, treatment, and prognosis of C tetani infections. PMID:27301930

  14. Genome-wide interaction analysis reveals replicated epistatic effects on brain structure

    PubMed Central

    Hibar, Derrek P.; Stein, Jason L.; Jahanshad, Neda; Kohannim, Omid; Hua, Xue; Toga, Arthur W.; McMahon, Katie L.; de Zubicaray, Greig I.; Martin, Nicholas G.; Wright, Margaret J.; Weiner, Michael W.; Thompson, Paul M.

    2015-01-01

    The discovery of several genes that affect risk for Alzheimer's disease ignited a worldwide search for Single Nucleotide Polymorphisms (SNPs), common genetic variants that affect the brain. Genome-wide search of all possible SNP-SNP interactions is challenging and rarely attempted, due to the complexity of conducting ∼1011 pairwise statistical tests. However, recent advances in machine learning, e.g., iterative sure independence screening (SIS), make it possible to analyze datasets with vastly more predictors than observations. Using an implementation of the SIS algorithm (called EPISIS), we performed a genome-wide interaction analysis testing all possible SNP-SNP interactions affecting regional brain volumes measured on MRI and mapped using tensor-based morphometry. We identified a significant SNP-SNP interaction between rs1345203 and rs1213205 that explains 1.9% of the variance in temporal lobe volume. We mapped the whole-brain, voxelwise effects of the interaction in the ADNI dataset and separately in an independent replication dataset of healthy twins (QTIM). Each additional loading in the interaction effect was associated with ∼5% greater brain regional brain volume (a protective effect) in both ADNI and QTIM samples. PMID:25264344

  15. Cytogenomic profiling of breast cancer brain metastases reveals potential for repurposing targeted therapeutics.

    PubMed

    Bollig-Fischer, Aliccia; Michelhaugh, Sharon K; Wijesinghe, Priyanga; Dyson, Greg; Kruger, Adele; Palanisamy, Nallasivam; Choi, Lydia; Alosh, Baraa; Ali-Fehmi, Rouba; Mittal, Sandeep

    2015-06-10

    Breast cancer brain metastases remain a significant clinical problem. Chemotherapy is ineffective and a lack of treatment options result in poor patient outcomes. Targeted therapeutics have proven to be highly effective in primary breast cancer, but lack of molecular genomic characterization of metastatic brain tumors is hindering the development of new treatment regimens. Here we contribute to fill this void by reporting on gene copy number variation (CNV) in 10 breast cancer metastatic brain tumors, assayed by array comparative genomic hybridization (aCGH). Results were compared to a list of cancer genes verified by others to influence cancer. Cancer gene aberrations were identified in all specimens and pathway-level analysis was applied to aggregate data, which identified stem cell pluripotency pathway enrichment and highlighted recurring, significant amplification of SOX2, PIK3CA, NTRK1, GNAS, CTNNB1, and FGFR1. For a subset of the metastatic brain tumor samples (n = 4) we compared patient-matched primary breast cancer specimens. The results of our CGH analysis and validation by alternative methods indicate that oncogenic signals driving growth of metastatic tumors exist in the original cancer. This report contributes support for more rapid development of new treatments of metastatic brain tumors, the use of genomic-based diagnostic tools and repurposed drug treatments.

  16. Revealing a Brain Network Endophenotype in Families with Idiopathic Generalised Epilepsy

    PubMed Central

    FitzGerald, Thomas H. B.; Elwes, Robert D. C.; Nashef, Lina; Terry, John R.; Richardson, Mark P.

    2014-01-01

    Idiopathic generalised epilepsy (IGE) has a genetic basis. The mechanism of seizure expression is not fully known, but is assumed to involve large-scale brain networks. We hypothesised that abnormal brain network properties would be detected using EEG in patients with IGE, and would be manifest as a familial endophenotype in their unaffected first-degree relatives. We studied 117 participants: 35 patients with IGE, 42 unaffected first-degree relatives, and 40 normal controls, using scalp EEG. Graph theory was used to describe brain network topology in five frequency bands for each subject. Frequency bands were chosen based on a published Spectral Factor Analysis study which demonstrated these bands to be optimally robust and independent. Groups were compared, using Bonferroni correction to account for nonindependent measures and multiple groups. Degree distribution variance was greater in patients and relatives than controls in the 6–9 Hz band (p = 0.0005, p = 0.0009 respectively). Mean degree was greater in patients than healthy controls in the 6–9 Hz band (p = 0.0064). Clustering coefficient was higher in patients and relatives than controls in the 6–9 Hz band (p = 0.0025, p = 0.0013). Characteristic path length did not differ between groups. No differences were found between patients and unaffected relatives. These findings suggest brain network topology differs between patients with IGE and normal controls, and that some of these network measures show similar deviations in patients and in unaffected relatives who do not have epilepsy. This suggests brain network topology may be an inherited endophenotype of IGE, present in unaffected relatives who do not have epilepsy, as well as in affected patients. We propose that abnormal brain network topology may be an endophenotype of IGE, though not in itself sufficient to cause epilepsy. PMID:25302690

  17. Separation methods that are capable of revealing blood-brain barrier permeability.

    PubMed

    Dash, Alekha K; Elmquist, William F

    2003-11-25

    The objective of this review is to emphasize the application of separation science in evaluating the blood-brain barrier (BBB) permeability to drugs and bioactive agents. Several techniques have been utilized to quantitate the BBB permeability. These methods can be classified into two major categories: in vitro or in vivo. The in vivo methods used include brain homogenization, cerebrospinal fluid (CSF) sampling, voltametry, autoradiography, nuclear magnetic resonance (NMR) spectroscopy, positron emission tomography (PET), intracerebral microdialysis, and brain uptake index (BUI) determination. The in vitro methods include tissue culture and immobilized artificial membrane (IAM) technology. Separation methods have always played an important role as adjunct methods to the methods outlined above for the quantitation of BBB permeability and have been utilized the most with brain homogenization, in situ brain perfusion, CSF sampling, intracerebral microdialysis, in vitro tissue culture and IAM chromatography. However, the literature published to date indicates that the separation method has been used the most in conjunction with intracerebral microdialysis and CSF sampling methods. The major advantages of microdialysis sampling in BBB permeability studies is the possibility of online separation and quantitation as well as the need for only a small sample volume for such an analysis. Separation methods are preferred over non-separation methods in BBB permeability evaluation for two main reasons. First, when the selectivity of a determination method is insufficient, interfering substances must be separated from the analyte of interest prior to determination. Secondly, when large number of analytes is to be detected and quantitated by a single analytical procedure, the mixture must be separated to each individual component prior to determination. Chiral separation in particular can be essential to evaluate the stereo-selective permeation and distribution of agents into the

  18. Unusual Adrenal and Brain Metastases From Follicular Thyroid Carcinoma Revealed by 131I SPECT/CT.

    PubMed

    Zhao, Zhen; Shen, Guo-hua; Liu, Bin; Kuang, An-ren

    2016-01-01

    The adrenal metastasis from differentiated thyroid carcinoma is uncommon. Metastatic involvement of both adrenal and brain in the same patient from differentiated thyroid carcinoma is rare. Here, we described an unusual case with iodine-avid lung, bone, adrenal, liver, and brain metastases from follicular thyroid carcinoma confirmed by 131I SPECT/CT. The utilization of SPECT/CT in thyroid cancer patients can detect the presence of metastases and also exclude potential false-positive lesions. Our case demonstrates that SPECT/CT is helpful in localizing and confirming metastatic lesions from differentiated thyroid carcinoma in rare and unusual sites.

  19. Unexpected light behaviour in periodic segmented waveguides

    NASA Astrophysics Data System (ADS)

    Aschiéri, Pierre; Doya, Valérie

    2011-12-01

    In this article, it is shown that multimode periodic segmented waveguides (PSW) are versatile optical systems in which properties of wave chaos can be highlighted. Numerical wave analysis reveals that structures of quantum phase space of PSW are similar to Poincaré sections which display a mixed phase space where stability islands are surrounded by a chaotic sea. Then, unexpected light behavior can occur such as, input gaussian beams do not diverge during the propagation in a highly multimode waveguide.

  20. Perceptual Shift in Bilingualism: Brain Potentials Reveal Plasticity in Pre-Attentive Colour Perception

    ERIC Educational Resources Information Center

    Athanasopoulos, Panos; Dering, Benjamin; Wiggett, Alison; Kuipers, Jan-Rouke; Thierry, Guillaume

    2010-01-01

    The validity of the linguistic relativity principle continues to stimulate vigorous debate and research. The debate has recently shifted from the behavioural investigation arena to a more biologically grounded field, in which tangible physiological evidence for language effects on perception can be obtained. Using brain potentials in a colour…

  1. Atypical Brain Responses to Reward Cues in Autism as Revealed by Event-Related Potentials

    ERIC Educational Resources Information Center

    Kohls, Gregor; Peltzer, Judith; Schulte-Ruther, Martin; Kamp-Becker, Inge; Remschmidt, Helmut; Herpertz-Dahlmann, Beate; Konrad, Kerstin

    2011-01-01

    Social motivation deficit theories suggest that children with autism do not properly anticipate and appreciate the pleasure of social stimuli. In this study, we investigated event-related brain potentials evoked by cues that triggered social versus monetary reward anticipation in children with autism. Children with autism showed attenuated P3…

  2. Event-Related Brain Potentials Reveal Anomalies in Temporal Processing of Faces in Autism Spectrum Disorder

    ERIC Educational Resources Information Center

    McPartland, James; Dawson, Geraldine; Webb, Sara J.; Panagiotides, Heracles; Carver, Leslie J.

    2004-01-01

    Background: Individuals with autism exhibit impairments in face recognition, and neuroimaging studies have shown that individuals with autism exhibit abnormal patterns of brain activity during face processing. The current study examined the temporal characteristics of face processing in autism and their relation to behavior. Method: High-density…

  3. Imaging studies in congenital anophthalmia reveal preservation of brain architecture in 'visual' cortex.

    PubMed

    Bridge, Holly; Cowey, Alan; Ragge, Nicola; Watkins, Kate

    2009-12-01

    The functional specialization of the human brain means that many regions are dedicated to processing a single sensory modality. When a modality is absent, as in congenital total blindness, 'visual' regions can be reliably activated by non-visual stimuli. The connections underlying this functional adaptation, however, remain elusive. In this study, using structural and diffusion-weighted magnetic resonance imaging, we investigated the structural differences in the brains of six bilaterally anophthalmic subjects compared with sighted subjects. Surprisingly, the gross structural differences in the brains were small, even in the occipital lobe where only a small region of the primary visual cortex showed a bilateral reduction in grey matter volume in the anophthalmic subjects compared with controls. Regions of increased cortical thickness were apparent on the banks of the Calcarine sulcus, but not in the fundus. Subcortically, the white matter volume around the optic tract and internal capsule in anophthalmic subjects showed a large decrease, yet the optic radiation volume did not differ significantly. However, the white matter integrity, as measured with fractional anisotropy showed an extensive reduction throughout the brain in the anophthalmic subjects, with the greatest difference in the optic radiations. In apparent contradiction to the latter finding, the connectivity between the lateral geniculate nucleus and primary visual cortex measured with diffusion tractography did not differ between the two populations. However, these findings can be reconciled by a demonstration that at least some of the reduction in fractional anisotropy in the optic radiation is due to an increase in the strength of fibres crossing the radiations. In summary, the major changes in the 'visual' brain in anophthalmic subjects may be subcortical, although the evidence of decreased fractional anisotropy and increased crossing fibres could indicate considerable re-organization.

  4. Multi-study Integration of Brain Cancer Transcriptomes Reveals Organ-Level Molecular Signatures

    PubMed Central

    Sung, Jaeyun; Kim, Pan-Jun; Ma, Shuyi; Funk, Cory C.; Magis, Andrew T.; Wang, Yuliang; Hood, Leroy; Geman, Donald; Price, Nathan D.

    2013-01-01

    We utilized abundant transcriptomic data for the primary classes of brain cancers to study the feasibility of separating all of these diseases simultaneously based on molecular data alone. These signatures were based on a new method reported herein – Identification of Structured Signatures and Classifiers (ISSAC) – that resulted in a brain cancer marker panel of 44 unique genes. Many of these genes have established relevance to the brain cancers examined herein, with others having known roles in cancer biology. Analyses on large-scale data from multiple sources must deal with significant challenges associated with heterogeneity between different published studies, for it was observed that the variation among individual studies often had a larger effect on the transcriptome than did phenotype differences, as is typical. For this reason, we restricted ourselves to studying only cases where we had at least two independent studies performed for each phenotype, and also reprocessed all the raw data from the studies using a unified pre-processing pipeline. We found that learning signatures across multiple datasets greatly enhanced reproducibility and accuracy in predictive performance on truly independent validation sets, even when keeping the size of the training set the same. This was most likely due to the meta-signature encompassing more of the heterogeneity across different sources and conditions, while amplifying signal from the repeated global characteristics of the phenotype. When molecular signatures of brain cancers were constructed from all currently available microarray data, 90% phenotype prediction accuracy, or the accuracy of identifying a particular brain cancer from the background of all phenotypes, was found. Looking forward, we discuss our approach in the context of the eventual development of organ-specific molecular signatures from peripheral fluids such as the blood. PMID:23935471

  5. Temporal Non-Local Means Filtering Reveals Real-Time Whole-Brain Cortical Interactions in Resting fMRI

    PubMed Central

    Bhushan, Chitresh; Chong, Minqi; Choi, Soyoung; Joshi, Anand A.; Haldar, Justin P.; Damasio, Hanna; Leahy, Richard M.

    2016-01-01

    Intensity variations over time in resting BOLD fMRI exhibit spatial correlation patterns consistent with a set of large scale cortical networks. However, visualizations of this data on the brain surface, even after extensive preprocessing, are dominated by local intensity fluctuations that obscure larger scale behavior. Our novel adaptation of non-local means (NLM) filtering, which we refer to as temporal NLM or tNLM, reduces these local fluctuations without the spatial blurring that occurs when using standard linear filtering methods. We show examples of tNLM filtering that allow direct visualization of spatio-temporal behavior on the cortical surface. These results reveal patterns of activity consistent with known networks as well as more complex dynamic changes within and between these networks. This ability to directly visualize brain activity may facilitate new insights into spontaneous brain dynamics. Further, temporal NLM can also be used as a preprocessor for resting fMRI for exploration of dynamic brain networks. We demonstrate its utility through application to graph-based functional cortical parcellation. Simulations with known ground truth functional regions demonstrate that tNLM filtering prior to parcellation avoids the formation of false parcels that can arise when using linear filtering. Application to resting fMRI data from the Human Connectome Project shows significant improvement, in comparison to linear filtering, in quantitative agreement with functional regions identified independently using task-based experiments as well as in test-retest reliability. PMID:27391481

  6. Temporal Non-Local Means Filtering Reveals Real-Time Whole-Brain Cortical Interactions in Resting fMRI.

    PubMed

    Bhushan, Chitresh; Chong, Minqi; Choi, Soyoung; Joshi, Anand A; Haldar, Justin P; Damasio, Hanna; Leahy, Richard M

    2016-01-01

    Intensity variations over time in resting BOLD fMRI exhibit spatial correlation patterns consistent with a set of large scale cortical networks. However, visualizations of this data on the brain surface, even after extensive preprocessing, are dominated by local intensity fluctuations that obscure larger scale behavior. Our novel adaptation of non-local means (NLM) filtering, which we refer to as temporal NLM or tNLM, reduces these local fluctuations without the spatial blurring that occurs when using standard linear filtering methods. We show examples of tNLM filtering that allow direct visualization of spatio-temporal behavior on the cortical surface. These results reveal patterns of activity consistent with known networks as well as more complex dynamic changes within and between these networks. This ability to directly visualize brain activity may facilitate new insights into spontaneous brain dynamics. Further, temporal NLM can also be used as a preprocessor for resting fMRI for exploration of dynamic brain networks. We demonstrate its utility through application to graph-based functional cortical parcellation. Simulations with known ground truth functional regions demonstrate that tNLM filtering prior to parcellation avoids the formation of false parcels that can arise when using linear filtering. Application to resting fMRI data from the Human Connectome Project shows significant improvement, in comparison to linear filtering, in quantitative agreement with functional regions identified independently using task-based experiments as well as in test-retest reliability. PMID:27391481

  7. Small RNA sequencing-microarray analyses in Parkinson leukocytes reveal deep brain stimulation-induced splicing changes that classify brain region transcriptomes

    PubMed Central

    Soreq, Lilach; Salomonis, Nathan; Bronstein, Michal; Greenberg, David S.; Israel, Zvi; Bergman, Hagai; Soreq, Hermona

    2013-01-01

    MicroRNAs (miRNAs) are key post transcriptional regulators of their multiple target genes. However, the detailed profile of miRNA expression in Parkinson's disease, the second most common neurodegenerative disease worldwide and the first motor disorder has not been charted yet. Here, we report comprehensive miRNA profiling by next-generation small-RNA sequencing, combined with targets inspection by splice-junction and exon arrays interrogating leukocyte RNA in Parkinson's disease patients before and after deep brain stimulation (DBS) treatment and of matched healthy control volunteers (HC). RNA-Seq analysis identified 254 miRNAs and 79 passenger strand forms as expressed in blood leukocytes, 16 of which were modified in patients pre-treatment as compared to HC. 11 miRNAs were modified following brain stimulation 5 of which were changed inversely to the disease induced changes. Stimulation cessation further induced changes in 11 miRNAs. Transcript isoform abundance analysis yielded 332 changed isoforms in patients compared to HC, which classified brain transcriptomes of 47 PD and control independent microarrays. Functional enrichment analysis highlighted mitochondrion organization. DBS induced 155 splice changes, enriched in ubiquitin homeostasis. Cellular composition analysis revealed immune cell activity pre and post treatment. Overall, 217 disease and 74 treatment alternative isoforms were predictably targeted by modified miRNAs within both 3′ and 5′ untranslated ends and coding sequence sites. The stimulation-induced network sustained 4 miRNAs and 7 transcripts of the disease network. We believe that the presented dynamic networks provide a novel avenue for identifying disease and treatment-related therapeutic targets. Furthermore, the identification of these networks is a major step forward in the road for understanding the molecular basis for neurological and neurodegenerative diseases and assessment of the impact of brain stimulation on human diseases

  8. Asymmetric neural coding revealed by in vivo calcium imaging in the honey bee brain

    PubMed Central

    Rigosi, Elisa; Haase, Albrecht; Rath, Lisa; Anfora, Gianfranco; Vallortigara, Giorgio; Szyszka, Paul

    2015-01-01

    Left–right asymmetries are common properties of nervous systems. Although lateralized sensory processing has been well studied, information is lacking about how asymmetries are represented at the level of neural coding. Using in vivo functional imaging, we identified a population-level left–right asymmetry in the honey bee's primary olfactory centre, the antennal lobe (AL). When both antennae were stimulated via a frontal odour source, the inter-odour distances between neural response patterns were higher in the right than in the left AL. Behavioural data correlated with the brain imaging results: bees with only their right antenna were better in discriminating a target odour in a cross-adaptation paradigm. We hypothesize that the differences in neural odour representations in the two brain sides serve to increase coding capacity by parallel processing. PMID:25673679

  9. Brain stimulation reveals crucial role of overcoming self-centeredness in self-control

    PubMed Central

    Soutschek, Alexander; Ruff, Christian C.; Strombach, Tina; Kalenscher, Tobias; Tobler, Philippe N.

    2016-01-01

    Neurobiological models of self-control predominantly focus on the role of prefrontal brain mechanisms involved in emotion regulation and impulse control. We provide evidence for an entirely different neural mechanism that promotes self-control by overcoming bias for the present self, a mechanism previously thought to be mainly important for interpersonal decision-making. In two separate studies, we show that disruptive transcranial magnetic stimulation (TMS) of the temporo-parietal junction—a brain region involved in overcoming one’s self-centered perspective—increases the discounting of delayed and prosocial rewards. This effect of TMS on temporal and social discounting is accompanied by deficits in perspective-taking and does not reflect altered spatial reorienting and number recognition. Our findings substantiate a fundamental commonality between the domains of self-control and social decision-making and highlight a novel aspect of the neurocognitive processes involved in self-control. PMID:27774513

  10. Shotgun brain proteomics reveals early molecular signature in presymptomatic mouse model of Alzheimer's disease.

    PubMed

    Yang, Hongqian; Wittnam, Jessica L; Zubarev, Roman A; Bayer, Thomas A

    2013-01-01

    AβpE3-42 (N-terminal truncated amyloid-β peptide starting with pyroglutamate at the third position) is abundant in Alzheimer's disease (AD) brain and has high aggregation propensity and cellular toxicity. Transgenic TBA42 mice expressing AβpE3-42 exhibit a neurological phenotype evident at the age of 12 months. As AD has a long presymptomatic period, early detection of imminent neurodegeneration is highly desirable. In the present work we used four-month-old presymptomatic TBA42 mice and performed a whole-brain proteome analysis in order to elucidate early AD-related pathological changes and the molecular networks involved. At least three proteins were found to be moderately (by 17% to 28%) but statistically significantly upregulated, including: nectin-like molecule 1 involved in cell-cell adhesion; Homer proteins involved in scaffolding, organizing proteins at synapse and regulating intracellular calcium within neurons; and inositol-trisphosphate 3-kinase A, which is important for InsP3 induced calcium signaling in the brain. Analysis of key nodes (regulatory molecules found on pathway intersections) identified Rho-kinase (ROCK), a serine/threonine kinase and one of the major downstream effectors of the small GTPase Rho, as well as three key nodes of the mTOR/p70S6K signaling pathway previously implicated in multiple fundamental biological processes including synaptic plasticity, and upregulated in AD. These data confirm that AD-typical molecular pathways can be detected by whole-brain shotgun proteomics in young presymptomatic mice long before the onset of behavioral changes. PMID:24018289

  11. Auditory information processing during human sleep as revealed by event-related brain potentials.

    PubMed

    Atienza, M; Cantero, J L; Escera, C

    2001-11-01

    The main goal of this review is to elucidate up to what extent pre-attentive auditory information processing is affected during human sleep. Evidence from event-related brain potential (ERP) studies indicates that auditory information processing is selectively affected, even at early phases, across the different stages of sleep-wakefulness continuum. According to these studies, 3 main conclusions are drawn: (1) the sleeping brain is able to automatically detect stimulus occurrence and trigger an orienting response towards that stimulus if its degree of novelty is large; (2) auditory stimuli are represented in the auditory system and maintained for a period of time in sensory memory, making the automatic-change detection during sleep possible; and (3) there are specific brain mechanisms (sleep-specific ERP components associated with the presence of vertex waves and K-complexes) by which information processing can be improved during non-rapid eye movement sleep. However, the remarkably affected amplitude and latency of the waking-ERPs during the different stages of sleep suggests deficits in the building and maintenance of a neural representation of the stimulus as well as in the process by which neural events lead to an orienting response toward such a stimulus. The deactivation of areas in the dorsolateral pre-frontal cortex during sleep contributing to the generation of these ERP components is hypothesized to be one of the main causes for the attenuated amplitude of these ERPs during human sleep. PMID:11682341

  12. Biostatistical analysis of gene microarrays reveals diverse expression clusters between macaque subspecies in brain SIV infection.

    PubMed

    Kneitz, S; Meisner, F; Sopper, S; Kaiser, F; Grünblatt, E; Scheller, C; Riederer, P; ter Meulen, V; Koutsilieri, E

    2007-01-01

    In this study we investigated differences in the gene expression profiling of the brains of rhesus macaques that were uninfected or infected with SIV in the asymptomatic stage or AIDS. The main aim was to use biostatistical methods to classify brain gene expression following SIV infection, without consideration of the biological significance of the individual genes. We also used data from animals treated with different pharmacological substances such as dopaminergic drugs, N-methyl-D-aspartate (NMDA) antagonists or antioxidants during the early stage of infection as these animals exhibited an accelerated or attenuated neuropsychiatric disease progression. We found macaque subspecies to be a more important factor for disease classification based on gene expression profiling than clinical symptoms or neuropathological findings. It is noteworthy that SIV-infected pharmacologically-treated. Chinese animals clustered near uninfected animals independent on the outcome of the treatment, whereas untreated SIV infected animals were clustered in a separate subtree. It is clear from this study that NeuroAIDS is a diverse disease entity and that SIV brain genes can be differentially regulated, depending on the disease type as well as changed dependent on the monkey subspecies.

  13. Exercise challenge in Gulf War Illness reveals two subgroups with altered brain structure and function.

    PubMed

    Rayhan, Rakib U; Stevens, Benson W; Raksit, Megna P; Ripple, Joshua A; Timbol, Christian R; Adewuyi, Oluwatoyin; VanMeter, John W; Baraniuk, James N

    2013-01-01

    Nearly 30% of the approximately 700,000 military personnel who served in Operation Desert Storm (1990-1991) have developed Gulf War Illness, a condition that presents with symptoms such as cognitive impairment, autonomic dysfunction, debilitating fatigue and chronic widespread pain that implicate the central nervous system. A hallmark complaint of subjects with Gulf War Illness is post-exertional malaise; defined as an exacerbation of symptoms following physical and/or mental effort. To study the causal relationship between exercise, the brain, and changes in symptoms, 28 Gulf War veterans and 10 controls completed an fMRI scan before and after two exercise stress tests to investigate serial changes in pain, autonomic function, and working memory. Exercise induced two clinical Gulf War Illness subgroups. One subgroup presented with orthostatic tachycardia (n = 10). This phenotype correlated with brainstem atrophy, baseline working memory compensation in the cerebellar vermis, and subsequent loss of compensation after exercise. The other subgroup developed exercise induced hyperalgesia (n = 18) that was associated with cortical atrophy and baseline working memory compensation in the basal ganglia. Alterations in cognition, brain structure, and symptoms were absent in controls. Our novel findings may provide an understanding of the relationship between the brain and post-exertional malaise in Gulf War Illness.

  14. High-throughput RNA sequencing reveals structural differences of orthologous brain-expressed genes between western lowland gorillas and humans.

    PubMed

    Lipovich, Leonard; Hou, Zhuo-Cheng; Jia, Hui; Sinkler, Christopher; McGowen, Michael; Sterner, Kirstin N; Weckle, Amy; Sugalski, Amara B; Pipes, Lenore; Gatti, Domenico L; Mason, Christopher E; Sherwood, Chet C; Hof, Patrick R; Kuzawa, Christopher W; Grossman, Lawrence I; Goodman, Morris; Wildman, Derek E

    2016-02-01

    The human brain and human cognitive abilities are strikingly different from those of other great apes despite relatively modest genome sequence divergence. However, little is presently known about the interspecies divergence in gene structure and transcription that might contribute to these phenotypic differences. To date, most comparative studies of gene structure in the brain have examined humans, chimpanzees, and macaque monkeys. To add to this body of knowledge, we analyze here the brain transcriptome of the western lowland gorilla (Gorilla gorilla gorilla), an African great ape species that is phylogenetically closely related to humans, but with a brain that is approximately one-third the size. Manual transcriptome curation from a sample of the planum temporale region of the neocortex revealed 12 protein-coding genes and one noncoding-RNA gene with exons in the gorilla unmatched by public transcriptome data from the orthologous human loci. These interspecies gene structure differences accounted for a total of 134 amino acids in proteins found in the gorilla that were absent from protein products of the orthologous human genes. Proteins varying in structure between human and gorilla were involved in immunity and energy metabolism, suggesting their relevance to phenotypic differences. This gorilla neocortical transcriptome comprises an empirical, not homology- or prediction-driven, resource for orthologous gene comparisons between human and gorilla. These findings provide a unique repository of the sequences and structures of thousands of genes transcribed in the gorilla brain, pointing to candidate genes that may contribute to the traits distinguishing humans from other closely related great apes. PMID:26132897

  15. High-throughput RNA sequencing reveals structural differences of orthologous brain-expressed genes between western lowland gorillas and humans.

    PubMed

    Lipovich, Leonard; Hou, Zhuo-Cheng; Jia, Hui; Sinkler, Christopher; McGowen, Michael; Sterner, Kirstin N; Weckle, Amy; Sugalski, Amara B; Pipes, Lenore; Gatti, Domenico L; Mason, Christopher E; Sherwood, Chet C; Hof, Patrick R; Kuzawa, Christopher W; Grossman, Lawrence I; Goodman, Morris; Wildman, Derek E

    2016-02-01

    The human brain and human cognitive abilities are strikingly different from those of other great apes despite relatively modest genome sequence divergence. However, little is presently known about the interspecies divergence in gene structure and transcription that might contribute to these phenotypic differences. To date, most comparative studies of gene structure in the brain have examined humans, chimpanzees, and macaque monkeys. To add to this body of knowledge, we analyze here the brain transcriptome of the western lowland gorilla (Gorilla gorilla gorilla), an African great ape species that is phylogenetically closely related to humans, but with a brain that is approximately one-third the size. Manual transcriptome curation from a sample of the planum temporale region of the neocortex revealed 12 protein-coding genes and one noncoding-RNA gene with exons in the gorilla unmatched by public transcriptome data from the orthologous human loci. These interspecies gene structure differences accounted for a total of 134 amino acids in proteins found in the gorilla that were absent from protein products of the orthologous human genes. Proteins varying in structure between human and gorilla were involved in immunity and energy metabolism, suggesting their relevance to phenotypic differences. This gorilla neocortical transcriptome comprises an empirical, not homology- or prediction-driven, resource for orthologous gene comparisons between human and gorilla. These findings provide a unique repository of the sequences and structures of thousands of genes transcribed in the gorilla brain, pointing to candidate genes that may contribute to the traits distinguishing humans from other closely related great apes.

  16. A mouse model for eukaryotic translation initiation factor 2B-leucodystrophy reveals abnormal development of brain white matter.

    PubMed

    Geva, Michal; Cabilly, Yuval; Assaf, Yaniv; Mindroul, Nina; Marom, Liraz; Raini, Gali; Pinchasi, Dalia; Elroy-Stein, Orna

    2010-08-01

    Eukaryotic translation initiation factor 2B is a major housekeeping complex that governs the rate of global protein synthesis under normal and stress conditions. Mutations in any of its five subunits lead to leucoencephalopathy with vanishing white matter, an inherited chronic-progressive fatal brain disease with unknown aetiology, which is among the most prevalent childhood white matter disorders. We generated the first animal model for the disease by introducing a point mutation into the mouse Eif2b5 gene locus, leading to R132H replacement corresponding to the clinically significant human R136H mutation in the catalytic subunit. In contrast to human patients, mice homozygous for the mutant Eif2b5 allele (Eif2b5(R132H/R132H) mice) enable multiple analyses under a defined genetic background during the pre-symptomatic stages and during recovery from a defined brain insult. Time-course magnetic resonance imaging revealed for the first time the delayed development of the brain white matter due to the mutation. Electron microscopy demonstrated a higher proportion of small-calibre nerve fibres. Immunohistochemistry detected an abnormal abundance of oligodendrocytes and astrocytes in the brain of younger animals, as well as an abnormal level of major myelin proteins. Most importantly, mutant mice failed to recover from cuprizone-induced demyelination, reflecting an increased sensitivity to brain insults. The anomalous development of white matter in Eif2b5(R132H/R132H) mice underscores the importance of tight translational control to normal myelin formation and maintenance.

  17. Prion Infection of Mouse Brain Reveals Multiple New Upregulated Genes Involved in Neuroinflammation or Signal Transduction

    PubMed Central

    Striebel, James F.; Race, Brent; Phillips, Katie; Chesebro, Bruce

    2014-01-01

    ABSTRACT Gliosis is often a preclinical pathological finding in neurodegenerative diseases, including prion diseases, but the mechanisms facilitating gliosis and neuronal damage in these diseases are not understood. To expand our knowledge of the neuroinflammatory response in prion diseases, we assessed the expression of key genes and proteins involved in the inflammatory response and signal transduction in mouse brain at various times after scrapie infection. In brains of scrapie-infected mice at pre- and postclinical stages, we identified 15 previously unreported differentially expressed genes related to inflammation or activation of the STAT signal transduction pathway. Levels for the majority of differentially expressed genes increased with time postinfection. In quantitative immunoblotting experiments of STAT proteins, STAT1α, phosphorylated-STAT1α (pSTAT1α), and pSTAT3 were increased between 94 and 131 days postinfection (p.i.) in brains of mice infected with strain 22L. Furthermore, a select group of STAT-associated genes was increased preclinically during scrapie infection, suggesting early activation of the STAT signal transduction pathway. Comparison of inflammatory markers between mice infected with scrapie strains 22L and RML indicated that the inflammatory responses and gene expression profiles in the brains were strikingly similar, even though these scrapie strains infect different brain regions. The endogenous interleukin-1 receptor antagonist (IL-1Ra), an inflammatory marker, was newly identified as increasing preclinically in our model and therefore might influence scrapie pathogenesis in vivo. However, in IL-1Ra-deficient or overexpressor transgenic mice inoculated with scrapie, neither loss nor overexpression of IL-1Ra demonstrated any observable effect on gliosis, protease-resistant prion protein (PrPres) formation, disease tempo, pathology, or expression of the inflammatory genes analyzed. IMPORTANCE Prion infection leads to Pr

  18. Unexpected molecular weight effect in polymer nanocomposites

    DOE PAGES

    Cheng, Shiwang; Holt, Adam P.; Wang, Huiqun; Fan, Fei; Bocharova, Vera; Martin, Halie J.; Etampawala, Thusitha N.; White, Benjamin Tyler; Saito, Tomonori; Kang, Nam -Goo; et al

    2016-01-22

    Here, the properties of the interfacial layer between the polymer matrix and nanoparticles largely determine the macroscopic properties of polymer nanocomposites (PNCs). Although the static thickness of the interfacial layer was found to increase with the molecular weight (MW), the influence of MW on segmental relaxation and the glass transition in this layer remains to be explored. In this Letter, we show an unexpected MW dependence of the interfacial properties in PNC with attractive polymer-nanoparticle interactions: the thickness of the interfacial layer with hindered segmental relaxation decreases as MW increases, in sharp constrast to theoretical predictions. Further analyses reveal amore » reduction in mass density of the interfacial layer with increasing MW, which can explain these unexpected dynamic effects. Our observations call for a significant revision of the current understandings of PNCs and suggest interesting ways to tailor their properties.« less

  19. Transcriptomic Analyses Reveal Novel Genes with Sexually Dimorphic Expression in Yellow Catfish (Pelteobagrus fulvidraco) Brain.

    PubMed

    Lu, Jianguo; Zheng, Min; Zheng, Jiajia; Liu, Jian; Liu, Yongzhuang; Peng, Lina; Wang, Pingping; Zhang, Xiaofeng; Wang, Qiushi; Luan, Peixian; Mahbooband, Shahid; Sun, Xiaowen

    2015-10-01

    Yellow catfish (Pelteobagrus fulvidraco) is a pivotal freshwater aquaculture species in China. It shows sexual size dimorphism favoring male in growth. Whole transcriptome approach is required to get the overview of genetic toolkit for understanding the sex determination mechanism aiming at devising its monosex production. Beside gonads, the brain is also considered as a major organ for vertebrate reproduction. Transcriptomic analyses on the brain and of different developmental stages will provide the dynamic view necessary for better understanding its sex determination. In this regard, we have performed a de novo assembly of yellow catfish brain transcriptome by high throughput Illumina sequencing. A total number of 154,507 contigs were obtained with the lengths ranging from 201 to 27,822 bp and N50 of 2,101 bp, as well as 20,699 unigenes were identified. Of these unigenes, 13 and 54 unigenes were detected to be XY-specifically expressed genes (SEGs) for one and 2-year-old yellow catfish, while the corresponding numbers of XX-SEGs for those two stages were 19 and 13, respectively. Our work identifies a set of annotated genes that are candidate factors affecting sexual dimorphism as well as simple sequence repeat (SSR) and single nucleotide variation (SNV) in yellow catfish. To validate the expression patterns of the sex-related genes, we performed quantitative real-time PCR (qRT-PCR) indicating the reliability and accuracy of our analysis. The results in our study may enhance our understanding of yellow catfish sex determination and potentially help to improve the production of all-male yellow catfish for aquaculture. PMID:26242754

  20. Large-scale brain network abnormalities in Huntington's disease revealed by structural covariance.

    PubMed

    Minkova, Lora; Eickhoff, Simon B; Abdulkadir, Ahmed; Kaller, Christoph P; Peter, Jessica; Scheller, Elisa; Lahr, Jacob; Roos, Raymund A; Durr, Alexandra; Leavitt, Blair R; Tabrizi, Sarah J; Klöppel, Stefan

    2016-01-01

    Huntington's disease (HD) is a progressive neurodegenerative disorder that can be diagnosed with certainty decades before symptom onset. Studies using structural MRI have identified grey matter (GM) loss predominantly in the striatum, but also involving various cortical areas. So far, voxel-based morphometric studies have examined each brain region in isolation and are thus unable to assess the changes in the interrelation of brain regions. Here, we examined the structural covariance in GM volumes in pre-specified motor, working memory, cognitive flexibility, and social-affective networks in 99 patients with manifest HD (mHD), 106 presymptomatic gene mutation carriers (pre-HD), and 108 healthy controls (HC). After correction for global differences in brain volume, we found that increased GM volume in one region was associated with increased GM volume in another. When statistically comparing the groups, no differences between HC and pre-HD were observed, but increased positive correlations were evident for mHD, relative to pre-HD and HC. These findings could be explained by a HD-related neuronal loss heterogeneously affecting the examined network at the pre-HD stage, which starts to dominate structural covariance globally at the manifest stage. Follow-up analyses identified structural connections between frontoparietal motor regions to be linearly modified by disease burden score (DBS). Moderator effects of disease load burden became significant at a DBS level typically associated with the onset of unequivocal HD motor signs. Together with existing findings from functional connectivity analyses, our data indicates a critical role of these frontoparietal regions for the onset of HD motor signs.

  1. Bilingualism at the core of the brain. Structural differences between bilinguals and monolinguals revealed by subcortical shape analysis.

    PubMed

    Burgaleta, Miguel; Sanjuán, Ana; Ventura-Campos, Noelia; Sebastian-Galles, Núria; Ávila, César

    2016-01-15

    Naturally acquiring a language shapes the human brain through a long-lasting learning and practice process. This is supported by previous studies showing that managing more than one language from early childhood has an impact on brain structure and function. However, to what extent bilingual individuals present neuroanatomical peculiarities at the subcortical level with respect to monolinguals is yet not well understood, despite the key role of subcortical gray matter for a number of language functions, including monitoring of speech production and language control - two processes especially solicited by bilinguals. Here we addressed this issue by performing a subcortical surface-based analysis in a sample of monolinguals and simultaneous bilinguals (N=88) that only differed in their language experience from birth. This analysis allowed us to study with great anatomical precision the potential differences in morphology of key subcortical structures, namely, the caudate, accumbens, putamen, globus pallidus and thalamus. Vertexwise analyses revealed significantly expanded subcortical structures for bilinguals compared to monolinguals, localized in bilateral putamen and thalamus, as well as in the left globus pallidus and right caudate nucleus. A topographical interpretation of our results suggests that a more complex phonological system in bilinguals may lead to a greater development of a subcortical brain network involved in monitoring articulatory processes.

  2. Bilingualism at the core of the brain. Structural differences between bilinguals and monolinguals revealed by subcortical shape analysis.

    PubMed

    Burgaleta, Miguel; Sanjuán, Ana; Ventura-Campos, Noelia; Sebastian-Galles, Núria; Ávila, César

    2016-01-15

    Naturally acquiring a language shapes the human brain through a long-lasting learning and practice process. This is supported by previous studies showing that managing more than one language from early childhood has an impact on brain structure and function. However, to what extent bilingual individuals present neuroanatomical peculiarities at the subcortical level with respect to monolinguals is yet not well understood, despite the key role of subcortical gray matter for a number of language functions, including monitoring of speech production and language control - two processes especially solicited by bilinguals. Here we addressed this issue by performing a subcortical surface-based analysis in a sample of monolinguals and simultaneous bilinguals (N=88) that only differed in their language experience from birth. This analysis allowed us to study with great anatomical precision the potential differences in morphology of key subcortical structures, namely, the caudate, accumbens, putamen, globus pallidus and thalamus. Vertexwise analyses revealed significantly expanded subcortical structures for bilinguals compared to monolinguals, localized in bilateral putamen and thalamus, as well as in the left globus pallidus and right caudate nucleus. A topographical interpretation of our results suggests that a more complex phonological system in bilinguals may lead to a greater development of a subcortical brain network involved in monitoring articulatory processes. PMID:26505300

  3. The connectivity of functional cores reveals different degrees of segregation and integration in the brain at rest.

    PubMed

    de Pasquale, Francesco; Sabatini, Umberto; Della Penna, Stefania; Sestieri, Carlo; Caravasso, Chiara Falletta; Formisano, Rita; Péran, Patrice

    2013-04-01

    The principles of functional specialization and integration in the resting brain are implemented in a complex system of specialized networks that share some degree of interaction. Recent studies have identified wider functional modules compared to previously defined networks and reported a small-world architecture of brain activity in which central nodes balance the pressure to evolve segregated pathways with the integration of local systems. The accurate identification of such central nodes is crucial but might be challenging for several reasons, e.g. inter-subject variability and physiological/pathological network plasticity, and recent works reported partially inconsistent results concerning the properties of these cortical hubs. Here, we applied a whole-brain data-driven approach to extract cortical functional cores and examined their connectivity from a resting state fMRI experiment on healthy subjects. Two main statistically significant cores, centered on the posterior cingulate cortex and the supplementary motor area, were extracted and their functional connectivity maps, thresholded at three statistical levels, revealed the presence of two complex systems. One system is consistent with the default mode network (DMN) and gradually connects to visual regions, the other centered on motor regions and gradually connects to more sensory-specific portions of cortex. These two large scale networks eventually converged to regions belonging to the medial aspect of the DMN, potentially allowing inter-network interactions. PMID:23220493

  4. Dissecting the social brain: Introducing the EmpaToM to reveal distinct neural networks and brain-behavior relations for empathy and Theory of Mind.

    PubMed

    Kanske, Philipp; Böckler, Anne; Trautwein, Fynn-Mathis; Singer, Tania

    2015-11-15

    Successful social interactions require both affect sharing (empathy) and understanding others' mental states (Theory of Mind, ToM). As these two functions have mostly been investigated in isolation, the specificity of the underlying neural networks and the relation of these networks to the respective behavioral indices could not be tested. Here, we present a novel fMRI paradigm (EmpaToM) that independently manipulates both empathy and ToM. Experiments 1a/b (N=90) validated the task with established empathy and ToM paradigms on a behavioral and neural level. Experiment 2 (N=178) employed the EmpaToM and revealed clearly separable neural networks including anterior insula for empathy and ventral temporoparietal junction for ToM. These distinct networks could be replicated in task-free resting state functional connectivity. Importantly, brain activity in these two networks specifically predicted the respective behavioral indices, that is, inter-individual differences in ToM related brain activity predicted inter-individual differences in ToM performance, but not empathic responding, and vice versa. Taken together, the validated EmpaToM allows separation of affective and cognitive routes to understanding others. It may thus benefit future clinical, developmental, and intervention studies on identifying selective impairments and improvement in specific components of social cognition.

  5. Brain Activation of Negative Feedback in Rule Acquisition Revealed in a Segmented Wisconsin Card Sorting Test

    PubMed Central

    Wang, Jing; Cao, Bihua; Cai, Xueli; Gao, Heming; Li, Fuhong

    2015-01-01

    The present study is to investigate the brain activation associated with the informative value of negative feedback in rule acquisition. In each trial of a segmented Wisconsin Card Sorting Test, participants were provided with three reference cards and one target card, and were asked to match one of three reference cards to the target card based on a classification rule. Participants received feedback after each match. Participants would acquire the rule after one negative feedback (1-NF condition) or two successive negative feedbacks (2-NF condition). The functional magnetic resonance imaging (fMRI) results indicated that lateral prefrontal-to-parietal cortices were more active in the 2-NF condition than in the 1-NF condition. The activation in the right lateral prefrontal cortex and left posterior parietal cortex increased gradually with the amount of negative feedback. These results demonstrate that the informative value of negative feedback in rule acquisition might be modulated by the lateral prefronto-parietal loop. PMID:26469519

  6. Simultaneous EEG-fMRI reveals brain networks underlying recognition memory ERP old/new effects.

    PubMed

    Hoppstädter, Michael; Baeuchl, Christian; Diener, Carsten; Flor, Herta; Meyer, Patric

    2015-08-01

    The mapping of event-related potentials (ERP) on functional magnetic resonance imaging (fMRI) data remains difficult as scalp electroencephalography (EEG) is assumed to be largely insensitive to deep brain structures. Simultaneous recordings of EEG and fMRI might be helpful in reconciling surface ERPs with hemodynamic activations in medial temporal lobe structures related to recognition memory. EEG and imaging studies provide evidence for two independent processes underlying recognition memory, namely recollection and familiarity. Recollection reflects the conscious retrieval of contextual information about a specific episode, while familiarity refers to an acontextual feeling of knowing. Both processes were related to two spatiotemporally different ERP effects, namely the early mid-frontal old/new effect (familiarity) and the late parietal old new effect (recollection). We conducted an exploratory simultaneous EEG-fMRI study using a recognition memory paradigm to investigate which brain activations are modulated in relation to the ERP old/new effects. To this end we examined 17 participants in a yes/no recognition task with word stimuli. Single-trial amplitudes of ERP old/new effects were related to the hemodynamic signal in an EEG-informed fMRI analysis for a subset of 12 subjects. FMRI activation in the right dorsolateral prefrontal cortex and the right intraparietal sulcus was associated with the amplitude of the early frontal old/new effect (350-550ms), and activation in the right posterior hippocampus, parahippocampal cortex and retrosplenial cortex was associated with the amplitude of the late parietal old new effect (580-750ms). These results provide the first direct link between electrophysiological and hemodynamic correlates of familiarity and recollection. Moreover, these findings in healthy subjects complement data from intracranial ERP recordings in epilepsy patients and lesion studies in hypoxia patients. PMID:25988228

  7. A Social Network Approach Reveals Associations between Mouse Social Dominance and Brain Gene Expression.

    PubMed

    So, Nina; Franks, Becca; Lim, Sean; Curley, James P

    2015-01-01

    Modelling complex social behavior in the laboratory is challenging and requires analyses of dyadic interactions occurring over time in a physically and socially complex environment. In the current study, we approached the analyses of complex social interactions in group-housed male CD1 mice living in a large vivarium. Intensive observations of social interactions during a 3-week period indicated that male mice form a highly linear and steep dominance hierarchy that is maintained by fighting and chasing behaviors. Individual animals were classified as dominant, sub-dominant or subordinate according to their David's Scores and I& SI ranking. Using a novel dynamic temporal Glicko rating method, we ascertained that the dominance hierarchy was stable across time. Using social network analyses, we characterized the behavior of individuals within 66 unique relationships in the social group. We identified two individual network metrics, Kleinberg's Hub Centrality and Bonacich's Power Centrality, as accurate predictors of individual dominance and power. Comparing across behaviors, we establish that agonistic, grooming and sniffing social networks possess their own distinctive characteristics in terms of density, average path length, reciprocity out-degree centralization and out-closeness centralization. Though grooming ties between individuals were largely independent of other social networks, sniffing relationships were highly predictive of the directionality of agonistic relationships. Individual variation in dominance status was associated with brain gene expression, with more dominant individuals having higher levels of corticotropin releasing factor mRNA in the medial and central nuclei of the amygdala and the medial preoptic area of the hypothalamus, as well as higher levels of hippocampal glucocorticoid receptor and brain-derived neurotrophic factor mRNA. This study demonstrates the potential and significance of combining complex social housing and intensive

  8. Diffusion tensor imaging of dolphin brains reveals direct auditory pathway to temporal lobe.

    PubMed

    Berns, Gregory S; Cook, Peter F; Foxley, Sean; Jbabdi, Saad; Miller, Karla L; Marino, Lori

    2015-07-22

    The brains of odontocetes (toothed whales) look grossly different from their terrestrial relatives. Because of their adaptation to the aquatic environment and their reliance on echolocation, the odontocetes' auditory system is both unique and crucial to their survival. Yet, scant data exist about the functional organization of the cetacean auditory system. A predominant hypothesis is that the primary auditory cortex lies in the suprasylvian gyrus along the vertex of the hemispheres, with this position induced by expansion of 'associative' regions in lateral and caudal directions. However, the precise location of the auditory cortex and its connections are still unknown. Here, we used a novel diffusion tensor imaging (DTI) sequence in archival post-mortem brains of a common dolphin (Delphinus delphis) and a pantropical dolphin (Stenella attenuata) to map their sensory and motor systems. Using thalamic parcellation based on traditionally defined regions for the primary visual (V1) and auditory cortex (A1), we found distinct regions of the thalamus connected to V1 and A1. But in addition to suprasylvian-A1, we report here, for the first time, the auditory cortex also exists in the temporal lobe, in a region near cetacean-A2 and possibly analogous to the primary auditory cortex in related terrestrial mammals (Artiodactyla). Using probabilistic tract tracing, we found a direct pathway from the inferior colliculus to the medial geniculate nucleus to the temporal lobe near the sylvian fissure. Our results demonstrate the feasibility of post-mortem DTI in archival specimens to answer basic questions in comparative neurobiology in a way that has not previously been possible and shows a link between the cetacean auditory system and those of terrestrial mammals. Given that fresh cetacean specimens are relatively rare, the ability to measure connectivity in archival specimens opens up a plethora of possibilities for investigating neuroanatomy in cetaceans and other species

  9. A Social Network Approach Reveals Associations between Mouse Social Dominance and Brain Gene Expression

    PubMed Central

    So, Nina; Franks, Becca; Lim, Sean; Curley, James P.

    2015-01-01

    Modelling complex social behavior in the laboratory is challenging and requires analyses of dyadic interactions occurring over time in a physically and socially complex environment. In the current study, we approached the analyses of complex social interactions in group-housed male CD1 mice living in a large vivarium. Intensive observations of social interactions during a 3-week period indicated that male mice form a highly linear and steep dominance hierarchy that is maintained by fighting and chasing behaviors. Individual animals were classified as dominant, sub-dominant or subordinate according to their David’s Scores and I& SI ranking. Using a novel dynamic temporal Glicko rating method, we ascertained that the dominance hierarchy was stable across time. Using social network analyses, we characterized the behavior of individuals within 66 unique relationships in the social group. We identified two individual network metrics, Kleinberg’s Hub Centrality and Bonacich’s Power Centrality, as accurate predictors of individual dominance and power. Comparing across behaviors, we establish that agonistic, grooming and sniffing social networks possess their own distinctive characteristics in terms of density, average path length, reciprocity out-degree centralization and out-closeness centralization. Though grooming ties between individuals were largely independent of other social networks, sniffing relationships were highly predictive of the directionality of agonistic relationships. Individual variation in dominance status was associated with brain gene expression, with more dominant individuals having higher levels of corticotropin releasing factor mRNA in the medial and central nuclei of the amygdala and the medial preoptic area of the hypothalamus, as well as higher levels of hippocampal glucocorticoid receptor and brain-derived neurotrophic factor mRNA. This study demonstrates the potential and significance of combining complex social housing and intensive

  10. Diffusion tensor imaging of dolphin brains reveals direct auditory pathway to temporal lobe

    PubMed Central

    Berns, Gregory S.; Cook, Peter F.; Foxley, Sean; Jbabdi, Saad; Miller, Karla L.; Marino, Lori

    2015-01-01

    The brains of odontocetes (toothed whales) look grossly different from their terrestrial relatives. Because of their adaptation to the aquatic environment and their reliance on echolocation, the odontocetes' auditory system is both unique and crucial to their survival. Yet, scant data exist about the functional organization of the cetacean auditory system. A predominant hypothesis is that the primary auditory cortex lies in the suprasylvian gyrus along the vertex of the hemispheres, with this position induced by expansion of ‘associative′ regions in lateral and caudal directions. However, the precise location of the auditory cortex and its connections are still unknown. Here, we used a novel diffusion tensor imaging (DTI) sequence in archival post-mortem brains of a common dolphin (Delphinus delphis) and a pantropical dolphin (Stenella attenuata) to map their sensory and motor systems. Using thalamic parcellation based on traditionally defined regions for the primary visual (V1) and auditory cortex (A1), we found distinct regions of the thalamus connected to V1 and A1. But in addition to suprasylvian-A1, we report here, for the first time, the auditory cortex also exists in the temporal lobe, in a region near cetacean-A2 and possibly analogous to the primary auditory cortex in related terrestrial mammals (Artiodactyla). Using probabilistic tract tracing, we found a direct pathway from the inferior colliculus to the medial geniculate nucleus to the temporal lobe near the sylvian fissure. Our results demonstrate the feasibility of post-mortem DTI in archival specimens to answer basic questions in comparative neurobiology in a way that has not previously been possible and shows a link between the cetacean auditory system and those of terrestrial mammals. Given that fresh cetacean specimens are relatively rare, the ability to measure connectivity in archival specimens opens up a plethora of possibilities for investigating neuroanatomy in cetaceans and other species

  11. Immunogold labeling reveals subcellular localisation of silica nanoparticles in a human blood-brain barrier model

    NASA Astrophysics Data System (ADS)

    Ye, Dong; Anguissola, Sergio; O'Neill, Tiina; Dawson, Kenneth A.

    2015-05-01

    Subcellular location of nanoparticles has been widely investigated with fluorescence microscopy, via fluorescently labeled antibodies to visualise target antigens in cells. However, fluorescence microscopy, such as confocal or live cell imaging, has generally limited 3D spatial resolution. Conventional electron microscopy can be useful in bridging resolution gap, but still not ideal in resolving subcellular organelle identities. Using the pre-embedding immunogold electron microscopic imaging, we performed accurate examination of the intracellular trafficking and gathered further evidence of transport mechanisms of silica nanoparticles across a human in vitro blood-brain barrier model. Our approach can effectively immunolocalise a variety of intracellular compartments and provide new insights into the uptake and subcellular transport of nanoparticles.Subcellular location of nanoparticles has been widely investigated with fluorescence microscopy, via fluorescently labeled antibodies to visualise target antigens in cells. However, fluorescence microscopy, such as confocal or live cell imaging, has generally limited 3D spatial resolution. Conventional electron microscopy can be useful in bridging resolution gap, but still not ideal in resolving subcellular organelle identities. Using the pre-embedding immunogold electron microscopic imaging, we performed accurate examination of the intracellular trafficking and gathered further evidence of transport mechanisms of silica nanoparticles across a human in vitro blood-brain barrier model. Our approach can effectively immunolocalise a variety of intracellular compartments and provide new insights into the uptake and subcellular transport of nanoparticles. Electronic supplementary information (ESI) available: Nanoparticle characterisation data, preservation of cellular structures, staining controls, optimisation of size amplification via the silver enhancement, and more imaging results from anti-clathrin and anti-caveolin 1

  12. Novel drug-regulated transcriptional networks in brain reveal pharmacological properties of psychotropic drugs

    PubMed Central

    2013-01-01

    Background Despite their widespread use, the biological mechanisms underlying the efficacy of psychotropic drugs are still incompletely known; improved understanding of these is essential for development of novel more effective drugs and rational design of therapy. Given the large number of psychotropic drugs available and their differential pharmacological effects, it would be important to establish specific predictors of response to various classes of drugs. Results To identify the molecular mechanisms that may initiate therapeutic effects, whole-genome expression profiling (using 324 Illumina Mouse WG-6 microarrays) of drug-induced alterations in the mouse brain was undertaken, with a focus on the time-course (1, 2, 4 and 8 h) of gene expression changes produced by eighteen major psychotropic drugs: antidepressants, antipsychotics, anxiolytics, psychostimulants and opioids. The resulting database is freely accessible at http://www.genes2mind.org. Bioinformatics approaches led to the identification of three main drug-responsive genomic networks and indicated neurobiological pathways that mediate the alterations in transcription. Each tested psychotropic drug was characterized by a unique gene network expression profile related to its neuropharmacological properties. Functional links that connect expression of the networks to the development of neuronal adaptations (MAPK signaling pathway), control of brain metabolism (adipocytokine pathway), and organization of cell projections (mTOR pathway) were found. Conclusions The comparison of gene expression alterations between various drugs opened a new means to classify the different psychoactive compounds and to predict their cellular targets; this is well exemplified in the case of tianeptine, an antidepressant with unknown mechanisms of action. This work represents the first proof-of-concept study of a molecular classification of psychoactive drugs. PMID:24010892

  13. Boomerang Returns Unexpectedly

    NASA Astrophysics Data System (ADS)

    White, Martin; Scott, Douglas; Pierpaoli, Elena

    2000-12-01

    Experimental study of the anisotropy in the cosmic microwave background (CMB) is gathering momentum. The eagerly awaited Boomerang results have lived up to expectations. They provide convincing evidence in favor of the standard paradigm: the universe is close to flat and with primordial fluctuations that are redolent of inflation. Further scrutiny reveals something even more exciting, however-two hints that there may be some unforeseen physical effects. First, the primary acoustic peak appears at slightly larger scales than expected. Although this may be explicable through a combination of mundane effects, we suggest that it is also prudent to consider the possibility that the universe might be marginally closed. The other hint is provided by a second peak, which appears less prominent than expected. This may indicate one of a number of possibilities, including increased damping length or tilted initial conditions, but also breaking of coherence or features in the initial power spectrum. Further data should test whether the current concordance model needs only to be tweaked, or to be enhanced in some fundamental way. A paper about a boomerang by an Australian and his mates.

  14. Down Syndrome Developmental Brain Transcriptome Reveals Defective Oligodendrocyte Differentiation and Myelination.

    PubMed

    Olmos-Serrano, Jose Luis; Kang, Hyo Jung; Tyler, William A; Silbereis, John C; Cheng, Feng; Zhu, Ying; Pletikos, Mihovil; Jankovic-Rapan, Lucija; Cramer, Nathan P; Galdzicki, Zygmunt; Goodliffe, Joseph; Peters, Alan; Sethares, Claire; Delalle, Ivana; Golden, Jeffrey A; Haydar, Tarik F; Sestan, Nenad

    2016-03-16

    Trisomy 21, or Down syndrome (DS), is the most common genetic cause of developmental delay and intellectual disability. To gain insight into the underlying molecular and cellular pathogenesis, we conducted a multi-region transcriptome analysis of DS and euploid control brains spanning from mid-fetal development to adulthood. We found genome-wide alterations in the expression of a large number of genes, many of which exhibited temporal and spatial specificity and were associated with distinct biological processes. In particular, we uncovered co-dysregulation of genes associated with oligodendrocyte differentiation and myelination that were validated via cross-species comparison to Ts65Dn trisomy mice. Furthermore, we show that hypomyelination present in Ts65Dn mice is in part due to cell-autonomous effects of trisomy on oligodendrocyte differentiation and results in slower neocortical action potential transmission. Together, these results identify defects in white matter development and function in DS, and they provide a transcriptional framework for further investigating DS neuropathogenesis. PMID:26924435

  15. TMS interference with primacy and recency mechanisms reveals bimodal episodic encoding in the human brain.

    PubMed

    Innocenti, Iglis; Cappa, Stefano F; Feurra, Matteo; Giovannelli, Fabio; Santarnecchi, Emiliano; Bianco, Giovanni; Cincotta, Massimo; Rossi, Simone

    2013-01-01

    A classic finding of the psychology of memory is the "serial position effect." Immediate free recall of a word list is more efficient for items presented early (primacy effect) or late (recency effect), with respect to those in the middle. In an event-related, randomized block design, we interfered with the encoding of unrelated words lists with brief trains of repetitive TMS (rTMS), applied coincidently with the acoustic presentation of each word to the left dorsolateral pFC, the left intraparietal lobe, and a control site (vertex). Interference of rTMS with encoding produced a clear-cut double dissociation on accuracy during immediate free recall. The primacy effect was selectively worsened by rTMS of the dorsolateral pFC, whereas recency was selectively worsened by rTMS of the intraparietal lobe. These results are in agreement with the double dissociation between short-term and long-term memory observed in neuropsychological patients and provide direct evidence of distinct cortical mechanisms of encoding in the human brain.

  16. Quantitative Proteomics of Sleep-Deprived Mouse Brains Reveals Global Changes in Mitochondrial Proteins

    PubMed Central

    Li, Tie-Mei; Zhang, Ju-en; Lin, Rui; Chen, She; Luo, Minmin; Dong, Meng-Qiu

    2016-01-01

    Sleep is a ubiquitous, tightly regulated, and evolutionarily conserved behavior observed in almost all animals. Prolonged sleep deprivation can be fatal, indicating that sleep is a physiological necessity. However, little is known about its core function. To gain insight into this mystery, we used advanced quantitative proteomics technology to survey the global changes in brain protein abundance. Aiming to gain a comprehensive profile, our proteomics workflow included filter-aided sample preparation (FASP), which increased the coverage of membrane proteins; tandem mass tag (TMT) labeling, for relative quantitation; and high resolution, high mass accuracy, high throughput mass spectrometry (MS). In total, we obtained the relative abundance ratios of 9888 proteins encoded by 6070 genes. Interestingly, we observed significant enrichment for mitochondrial proteins among the differentially expressed proteins. This finding suggests that sleep deprivation strongly affects signaling pathways that govern either energy metabolism or responses to mitochondrial stress. Additionally, the differentially-expressed proteins are enriched in pathways implicated in age-dependent neurodegenerative diseases, including Parkinson’s, Huntington’s, and Alzheimer’s, hinting at possible connections between sleep loss, mitochondrial stress, and neurodegeneration. PMID:27684481

  17. Differences in brain circuitry for appetitive and reactive aggression as revealed by realistic auditory scripts

    PubMed Central

    Moran, James K.; Weierstall, Roland; Elbert, Thomas

    2014-01-01

    Aggressive behavior is thought to divide into two motivational elements: The first being a self-defensively motivated aggression against threat and a second, hedonically motivated “appetitive” aggression. Appetitive aggression is the less understood of the two, often only researched within abnormal psychology. Our approach is to understand it as a universal and adaptive response, and examine the functional neural activity of ordinary men (N = 50) presented with an imaginative listening task involving a murderer describing a kill. We manipulated motivational context in a between-subjects design to evoke appetitive or reactive aggression, against a neutral control, measuring activity with Magnetoencephalography (MEG). Results show differences in left frontal regions in delta (2–5 Hz) and alpha band (8–12 Hz) for aggressive conditions and right parietal delta activity differentiating appetitive and reactive aggression. These results validate the distinction of reward-driven appetitive aggression from reactive aggression in ordinary populations at the level of functional neural brain circuitry. PMID:25538590

  18. The neural bases for devaluing radical political statements revealed by penetrating traumatic brain injury.

    PubMed

    Cristofori, Irene; Viola, Vanda; Chau, Aileen; Zhong, Wanting; Krueger, Frank; Zamboni, Giovanna; Grafman, Jordan

    2015-08-01

    Given the determinant role of ventromedial prefrontal cortex (vmPFC) in valuation, we examined whether vmPFC lesions also modulate how people scale political beliefs. Patients with penetrating traumatic brain injury (pTBI; N = 102) and healthy controls (HCs; N = 31) were tested on the political belief task, where they rated 75 statements expressing political opinions concerned with welfare, economy, political involvement, civil rights, war and security. Each statement was rated for level of agreement and scaled along three dimensions: radicalism, individualism and conservatism. Voxel-based lesion-symptom mapping (VLSM) analysis showed that diminished scores for the radicalism dimension (i.e. statements were rated as less radical than the norms) were associated with lesions in bilateral vmPFC. After dividing the pTBI patients into three groups, according to lesion location (i.e. vmPFC, dorsolateral prefrontal cortex [dlPFC] and parietal cortex), we found that the vmPFC, but not the dlPFC, group had reduced radicalism scores compared with parietal and HC groups. These findings highlight the crucial role of the vmPFC in appropriately valuing political behaviors and may explain certain inappropriate social judgments observed in patients with vmPFC lesions. PMID:25656509

  19. The neural bases for devaluing radical political statements revealed by penetrating traumatic brain injury.

    PubMed

    Cristofori, Irene; Viola, Vanda; Chau, Aileen; Zhong, Wanting; Krueger, Frank; Zamboni, Giovanna; Grafman, Jordan

    2015-08-01

    Given the determinant role of ventromedial prefrontal cortex (vmPFC) in valuation, we examined whether vmPFC lesions also modulate how people scale political beliefs. Patients with penetrating traumatic brain injury (pTBI; N = 102) and healthy controls (HCs; N = 31) were tested on the political belief task, where they rated 75 statements expressing political opinions concerned with welfare, economy, political involvement, civil rights, war and security. Each statement was rated for level of agreement and scaled along three dimensions: radicalism, individualism and conservatism. Voxel-based lesion-symptom mapping (VLSM) analysis showed that diminished scores for the radicalism dimension (i.e. statements were rated as less radical than the norms) were associated with lesions in bilateral vmPFC. After dividing the pTBI patients into three groups, according to lesion location (i.e. vmPFC, dorsolateral prefrontal cortex [dlPFC] and parietal cortex), we found that the vmPFC, but not the dlPFC, group had reduced radicalism scores compared with parietal and HC groups. These findings highlight the crucial role of the vmPFC in appropriately valuing political behaviors and may explain certain inappropriate social judgments observed in patients with vmPFC lesions.

  20. The neural bases for devaluing radical political statements revealed by penetrating traumatic brain injury

    PubMed Central

    Cristofori, Irene; Viola, Vanda; Chau, Aileen; Zhong, Wanting; Krueger, Frank; Zamboni, Giovanna; Grafman, Jordan

    2015-01-01

    Given the determinant role of ventromedial prefrontal cortex (vmPFC) in valuation, we examined whether vmPFC lesions also modulate how people scale political beliefs. Patients with penetrating traumatic brain injury (pTBI; N = 102) and healthy controls (HCs; N = 31) were tested on the political belief task, where they rated 75 statements expressing political opinions concerned with welfare, economy, political involvement, civil rights, war and security. Each statement was rated for level of agreement and scaled along three dimensions: radicalism, individualism and conservatism. Voxel-based lesion-symptom mapping (VLSM) analysis showed that diminished scores for the radicalism dimension (i.e. statements were rated as less radical than the norms) were associated with lesions in bilateral vmPFC. After dividing the pTBI patients into three groups, according to lesion location (i.e. vmPFC, dorsolateral prefrontal cortex [dlPFC] and parietal cortex), we found that the vmPFC, but not the dlPFC, group had reduced radicalism scores compared with parietal and HC groups. These findings highlight the crucial role of the vmPFC in appropriately valuing political behaviors and may explain certain inappropriate social judgments observed in patients with vmPFC lesions. PMID:25656509

  1. Longitudinal MRI reveals altered trajectory of brain development during childhood and adolescence in fetal alcohol spectrum disorders.

    PubMed

    Treit, Sarah; Lebel, Catherine; Baugh, Lauren; Rasmussen, Carmen; Andrew, Gail; Beaulieu, Christian

    2013-06-12

    Diffusion tensor imaging (DTI) of brain development in fetal alcohol spectrum disorders (FASD) has revealed structural abnormalities, but studies have been limited by the use of cross-sectional designs. Longitudinal scans can provide key insights into trajectories of neurodevelopment within individuals with this common developmental disorder. Here we evaluate serial DTI and T1-weighted volumetric MRI in a human sample of 17 participants with FASD and 27 controls aged 5-15 years who underwent 2-3 scans each, ∼2-4 years apart (92 scans total). Increases of fractional anisotropy and decreases of mean diffusivity (MD) were observed between scans for both groups, in keeping with changes expected of typical development, but mixed-models analysis revealed significant age-by-group interactions for three major white matter tracts: superior longitudinal fasciculus and superior and inferior fronto-occipital fasciculus. These findings indicate altered developmental progression in these frontal-association tracts, with the FASD group notably showing greater reduction of MD between scans. ΔMD is shown to correlate with reading and receptive vocabulary in the FASD group, with steeper decreases of MD in the superior fronto-occipital fasciculus and superior longitudinal fasciculus between scans correlating with greater improvement in language scores. Volumetric analysis revealed reduced total brain, white, cortical gray, and deep gray matter volumes and fewer significant age-related volume increases in the FASD group, although age-by-group interactions were not significant. Longitudinal DTI indicates delayed white matter development during childhood and adolescence in FASD, which may underlie persistent or worsening behavioral and cognitive deficits during this critical period.

  2. Tantalizing Thanatos: unexpected links in death pathways.

    PubMed

    Cohen, Isabelle; Castedo, Maria; Kroemer, Guido

    2002-07-01

    Cell death is most frequently the result of apoptosis, an event that is often controlled by mitochondrial membrane permeabilization (MMP). Recent data reveal unexpected functional links between apoptosis and autophagic cell death, in the sense that MMP can trigger autophagy of damaged mitochondria. Conversely, one of the major signal-transducing molecules involved in the activation of autophagy during apoptosis--the so-called DAP kinase--can induce cell death through MMP. Connections are also emerging between apoptosis, autophagy, replicative senescence and cancer-specific metabolic changes. PMID:12185842

  3. PCNA immunoreactivity revealing normal proliferative activity in the brain of adult Lampetra planeri (Bloch, 1784).

    PubMed

    Margotta, Vito; Caronti, Brunella; Colombari, Paolo Tito; Castiglia, Riccardo

    2007-01-01

    It is now well known that the Teleosts among Osteichthyes, Urodele and Anuran Amphibians, Lacertilian Reptiles possess encephalic natural proliferative activities even into adulthood, as demonstrated by a great number of researches performed both under normal and various experimental conditions. Few years ago we have undertaken in adult heterothermic vertebrates a reappraisal on spontaneous cerebral proliferative events involving some organisms (Podarcis sicula, Triturus carnifex, Rana esculenta, Carassius carassius) representative of these vertebrates and belonging to the same or phylogenetically similar species used by previous researchers in studies having the same object. In our investigations, these performances were revealed by a proliferative immunocytochemical marker, the Proliferating Cell Nuclear Antigen (PCNA). At this point of our study in the scenario emerging from findings a missing piece is represented by Petromyzontidae. To fill up this gap in the present investigation, using our usual test, we have paid attention to adult specimens of Lampetra planeri. The obtained immunostaining panorama has revealed the presence of a considerable number of spontaneous proliferative activities. These events might differ in quantity, in various encephalic districts. PCNA-labelled cells appeared scattered in the cranial portion of olfactory bulbs, while the PCNA expression has been observed steadily localized with a distinctly continous distribution in cells interposed among the ependymal epithelium which lines the cavities of the proximal portion of the olfactory region and of the cerebral ventricles. DNA synthesis activity has been also found in cells scattered in the telencephalic, diencephalic, mesencephalic and medulla oblongata periventricular grey. This immunoreactivity was not revealable in the cerebellum. Our findings are discussed in the light of bibliographic news.

  4. DNA methylation analysis of the autistic brain reveals multiple dysregulated biological pathways

    PubMed Central

    Nardone, S; Sharan Sams, D; Reuveni, E; Getselter, D; Oron, O; Karpuj, M; Elliott, E

    2014-01-01

    Autism spectrum disorders (ASD) are a group of neurodevelopmental conditions characterized by dysfunction in social interaction, communication and stereotypic behavior. Genetic and environmental factors have been implicated in the development of ASD, but the molecular mechanisms underlying their interaction are not clear. Epigenetic modifications have been suggested as molecular mechanism that can mediate the interaction between the environment and the genome to produce adaptive or maladaptive behaviors. Here, using the Illumina 450 K methylation array we have determined the existence of many dysregulated CpGs in two cortical regions, Brodmann area 10 (BA10) and Brodmann area 24 (BA24), of individuals who had ASD. In BA10 we found a very significant enrichment for genomic areas responsible for immune functions among the hypomethylated CpGs, whereas genes related to synaptic membrane were enriched among hypermethylated CpGs. By comparing our methylome data with previously published transcriptome data, and by performing real-time PCR on selected genes that were dysregulated in our study, we show that hypomethylated genes are often overexpressed, and that there is an inverse correlation between gene expression and DNA methylation within the individuals. Among these genes there were C1Q, C3, ITGB2 (C3R), TNF-α, IRF8 and SPI1, which have recently been implicated in synaptic pruning and microglial cell specification. Finally, we determined the epigenetic dysregulation of the gene HDAC4, and we confirm that the locus encompassing C11orf21/TSPAN32 has multiple hypomethylated CpGs in the autistic brain, as previously demonstrated. Our data suggest a possible role for epigenetic processes in the etiology of ASD. PMID:25180572

  5. Comprehensive Glycomics of a Multistep Human Brain Tumor Model Reveals Specific Glycosylation Patterns Related to Malignancy

    PubMed Central

    Okada, Kazue; Kimura, Taichi; Piao, Jinhua; Tanaka, Shinya; Shinohara, Yasuro

    2015-01-01

    Cancer cells frequently express glycans at different levels and/or with fundamentally different structures from those expressed by normal cells, and therefore elucidation and manipulation of these glycosylations may provide a beneficial approach to cancer therapy. However, the relationship between altered glycosylation and causal genetic alteration(s) is only partially understood. Here, we employed a unique approach that applies comprehensive glycomic analysis to a previously described multistep tumorigenesis model. Normal human astrocytes were transformed via the serial introduction of hTERT, SV40ER, H-RasV12, and myrAKT, thereby mimicking human brain tumor grades I-IV. More than 160 glycans derived from three major classes of cell surface glycoconjugates (N- and O-glycans on glycoproteins, and glycosphingolipids) were quantitatively explored, and specific glycosylation patterns related to malignancy were systematically identified. The sequential introduction of hTERT, SV40ER, H-RasV12, and myrAKT led to (i) temporal expression of pauci-mannose/mono-antennary type N-glycans and GD3 (hTERT); (ii) switching from ganglio- to globo-series glycosphingolipids and the appearance of Neu5Gc (hTERT and SV40ER); (iii) temporal expression of bisecting GlcNAc residues, α2,6-sialylation, and stage-specific embryonic antigen-4, accompanied by suppression of core 2 O-glycan biosynthesis (hTERT, SV40ER and Ras); and (iv) increased expression of (neo)lacto-series glycosphingolipids and fucosylated N-glycans (hTERT, SV40ER, Ras and AKT). These sequential and transient glycomic alterations may be useful for tumor grade diagnosis and tumor prognosis, and also for the prediction of treatment response. PMID:26132161

  6. Optical Brain Imaging Reveals General Auditory and Language-Specific Processing in Early Infant Development

    PubMed Central

    Minagawa-Kawai, Yasuyo; van der Lely, Heather; Ramus, Franck; Sato, Yutaka; Mazuka, Reiko; Dupoux, Emmanuel

    2011-01-01

    This study uses near-infrared spectroscopy in young infants in order to elucidate the nature of functional cerebral processing for speech. Previous imaging studies of infants’ speech perception revealed left-lateralized responses to native language. However, it is unclear if these activations were due to language per se rather than to some low-level acoustic correlate of spoken language. Here we compare native (L1) and non-native (L2) languages with 3 different nonspeech conditions including emotional voices, monkey calls, and phase scrambled sounds that provide more stringent controls. Hemodynamic responses to these stimuli were measured in the temporal areas of Japanese 4 month-olds. The results show clear left-lateralized responses to speech, prominently to L1, as opposed to various activation patterns in the nonspeech conditions. Furthermore, implementing a new analysis method designed for infants, we discovered a slower hemodynamic time course in awake infants. Our results are largely explained by signal-driven auditory processing. However, stronger activations to L1 than to L2 indicate a language-specific neural factor that modulates these responses. This study is the first to discover a significantly higher sensitivity to L1 in 4 month-olds and reveals a neural precursor of the functional specialization for the higher cognitive network. PMID:20497946

  7. Multiple knockout mouse models reveal lincRNAs are required for life and brain development

    PubMed Central

    Sauvageau, Martin; Goff, Loyal A; Lodato, Simona; Bonev, Boyan; Groff, Abigail F; Gerhardinger, Chiara; Sanchez-Gomez, Diana B; Hacisuleyman, Ezgi; Li, Eric; Spence, Matthew; Liapis, Stephen C; Mallard, William; Morse, Michael; Swerdel, Mavis R; D’Ecclessis, Michael F; Moore, Jennifer C; Lai, Venus; Gong, Guochun; Yancopoulos, George D; Frendewey, David; Kellis, Manolis; Hart, Ronald P; Valenzuela, David M; Arlotta, Paola; Rinn, John L

    2013-01-01

    Many studies are uncovering functional roles for long noncoding RNAs (lncRNAs), yet few have been tested for in vivo relevance through genetic ablation in animal models. To investigate the functional relevance of lncRNAs in various physiological conditions, we have developed a collection of 18 lncRNA knockout strains in which the locus is maintained transcriptionally active. Initial characterization revealed peri- and postnatal lethal phenotypes in three mutant strains (Fendrr, Peril, and Mdgt), the latter two exhibiting incomplete penetrance and growth defects in survivors. We also report growth defects for two additional mutant strains (linc–Brn1b and linc–Pint). Further analysis revealed defects in lung, gastrointestinal tract, and heart in Fendrr−/− neonates, whereas linc–Brn1b−/− mutants displayed distinct abnormalities in the generation of upper layer II–IV neurons in the neocortex. This study demonstrates that lncRNAs play critical roles in vivo and provides a framework and impetus for future larger-scale functional investigation into the roles of lncRNA molecules. DOI: http://dx.doi.org/10.7554/eLife.01749.001 PMID:24381249

  8. Multiplex Brain Proteomic Analysis Revealed the Molecular Therapeutic Effects of Buyang Huanwu Decoction on Cerebral Ischemic Stroke Mice

    PubMed Central

    Shiao, Young-Ji; Liou, Kuo-Tong; Hsu, Wei-Hsiang; Hsieh, Pei-Hsuan; Lee, Chi-Ying; Chen, Yet-Ran; Lin, Yun-Lian

    2015-01-01

    Stroke is the second-leading cause of death worldwide, and tissue plasminogen activator (TPA) is the only drug used for a limited group of stroke patients in the acute phase. Buyang Huanwu Decoction (BHD), a traditional Chinese medicine prescription, has long been used for improving neurological functional recovery in stroke. In this study, we characterized the therapeutic effect of TPA and BHD in a cerebral ischemia/reperfusion (CIR) injury mouse model using multiplex proteomics approach. After the iTRAQ-based proteomics analysis, 1310 proteins were identified from the mouse brain with <1% false discovery rate. Among them, 877 quantitative proteins, 10.26% (90/877), 1.71% (15/877), and 2.62% (23/877) of the proteins was significantly changed in the CIR, BHD treatment, and TPA treatment, respectively. Functional categorization analysis showed that BHD treatment preserved the integrity of the blood–brain barrier (BBB) (Alb, Fga, and Trf), suppressed excitotoxicity (Grm5, Gnai, and Gdi), and enhanced energy metabolism (Bdh), thereby revealing its multiple effects on ischemic stroke mice. Moreover, the neurogenesis marker doublecortin was upregulated, and the activity of glycogen synthase kinase 3 (GSK-3) and Tau was inhibited, which represented the neuroprotective effects. However, TPA treatment deteriorated BBB breakdown. This study highlights the potential of BHD in clinical applications for ischemic stroke. PMID:26492191

  9. Multiplex Brain Proteomic Analysis Revealed the Molecular Therapeutic Effects of Buyang Huanwu Decoction on Cerebral Ischemic Stroke Mice.

    PubMed

    Chen, Hong-Jhang; Shen, Yuh-Chiang; Shiao, Young-Ji; Liou, Kuo-Tong; Hsu, Wei-Hsiang; Hsieh, Pei-Hsuan; Lee, Chi-Ying; Chen, Yet-Ran; Lin, Yun-Lian

    2015-01-01

    Stroke is the second-leading cause of death worldwide, and tissue plasminogen activator (TPA) is the only drug used for a limited group of stroke patients in the acute phase. Buyang Huanwu Decoction (BHD), a traditional Chinese medicine prescription, has long been used for improving neurological functional recovery in stroke. In this study, we characterized the therapeutic effect of TPA and BHD in a cerebral ischemia/reperfusion (CIR) injury mouse model using multiplex proteomics approach. After the iTRAQ-based proteomics analysis, 1310 proteins were identified from the mouse brain with <1% false discovery rate. Among them, 877 quantitative proteins, 10.26% (90/877), 1.71% (15/877), and 2.62% (23/877) of the proteins was significantly changed in the CIR, BHD treatment, and TPA treatment, respectively. Functional categorization analysis showed that BHD treatment preserved the integrity of the blood-brain barrier (BBB) (Alb, Fga, and Trf), suppressed excitotoxicity (Grm5, Gnai, and Gdi), and enhanced energy metabolism (Bdh), thereby revealing its multiple effects on ischemic stroke mice. Moreover, the neurogenesis marker doublecortin was upregulated, and the activity of glycogen synthase kinase 3 (GSK-3) and Tau was inhibited, which represented the neuroprotective effects. However, TPA treatment deteriorated BBB breakdown. This study highlights the potential of BHD in clinical applications for ischemic stroke. PMID:26492191

  10. The time course of action and action-word comprehension in the human brain as revealed by neurophysiology.

    PubMed

    Hauk, O; Shtyrov, Y; Pulvermüller, F

    2008-01-01

    Numerous previous neuroimaging studies suggest an involvement of cortical motor areas not only in action execution but also in action recognition and understanding. Motor areas of the human brain have also been found to activate during the processing of written and spoken action-related words and sentences. Even more strikingly, stimuli referring to different bodily effectors produced specific somatotopic activation patterns in the motor areas. However, metabolic neuroimaging results can be ambiguous with respect to the processing stage they reflect. This is a serious limitation when hypotheses concerning linguistic processes are tested, since in this case it is usually crucial to distinguish early lexico-semantic processing from strategic effects or mental imagery that may follow lexico-semantic information access. Timing information is therefore pivotal to determine the functional significance of motor areas in action recognition and action-word comprehension. Here, we review attempts to reveal the time course of these processes using neurophysiological methods (EEG, MEG and TMS), in visual and auditory domains. We will highlight the importance of the choice of appropriate paradigms in combination with the corresponding method for the extraction of timing information. The findings will be discussed in the general context of putative brain mechanisms of word and object recognition.

  11. Imaging by Elemental and Molecular Mass Spectrometry Reveals the Uptake of an Arsenolipid in the Brain of Drosophila melanogaster.

    PubMed

    Niehoff, Ann-Christin; Schulz, Jacqueline; Soltwisch, Jens; Meyer, Sören; Kettling, Hans; Sperling, Michael; Jeibmann, Astrid; Dreisewerd, Klaus; Francesconi, Kevin A; Schwerdtle, Tanja; Karst, Uwe

    2016-05-17

    Arsenic-containing lipids (arsenolipids) are natural products of marine organisms such as fish, invertebrates, and algae, many of which are important seafoods. A major group of arsenolipids, namely, the arsenic-containing hydrocarbons (AsHC), have recently been shown to be cytotoxic to human liver and bladder cells, a result that has stimulated interest in the chemistry and toxicology of these compounds. In this study, elemental laser ablation-inductively coupled plasma mass spectrometry (LA-ICPMS) and molecular matrix-assisted laser desorption/ionization (MALDI-)MS were used to image and quantify the uptake of an AsHC in the model organism Drosophila melanogaster. Using these two complementary methods, both an enrichment of arsenic and the presence of the AsHC in the brain were revealed, indicating that the intact arsenolipid had crossed the blood-brain barrier. Simultaneous acquisition of quantitative elemental concentrations and molecular distributions could allow new insight into organ-specific enrichment and possible transportation processes of arsenic-containing bioactive compounds in living organisms. PMID:27098356

  12. Imaging by Elemental and Molecular Mass Spectrometry Reveals the Uptake of an Arsenolipid in the Brain of Drosophila melanogaster.

    PubMed

    Niehoff, Ann-Christin; Schulz, Jacqueline; Soltwisch, Jens; Meyer, Sören; Kettling, Hans; Sperling, Michael; Jeibmann, Astrid; Dreisewerd, Klaus; Francesconi, Kevin A; Schwerdtle, Tanja; Karst, Uwe

    2016-05-17

    Arsenic-containing lipids (arsenolipids) are natural products of marine organisms such as fish, invertebrates, and algae, many of which are important seafoods. A major group of arsenolipids, namely, the arsenic-containing hydrocarbons (AsHC), have recently been shown to be cytotoxic to human liver and bladder cells, a result that has stimulated interest in the chemistry and toxicology of these compounds. In this study, elemental laser ablation-inductively coupled plasma mass spectrometry (LA-ICPMS) and molecular matrix-assisted laser desorption/ionization (MALDI-)MS were used to image and quantify the uptake of an AsHC in the model organism Drosophila melanogaster. Using these two complementary methods, both an enrichment of arsenic and the presence of the AsHC in the brain were revealed, indicating that the intact arsenolipid had crossed the blood-brain barrier. Simultaneous acquisition of quantitative elemental concentrations and molecular distributions could allow new insight into organ-specific enrichment and possible transportation processes of arsenic-containing bioactive compounds in living organisms.

  13. Non-parametric permutation thresholding for adaptive nonlinear beamformer analysis on MEG revealed oscillatory neuronal dynamics in human brain.

    PubMed

    Ishii, Ryouhei; Canuet, Leonides; Aoki, Yasunori; Ikeda, Shunichiro; Hata, Masahiro; Iwase, Masao; Takeda, Masatoshi

    2013-01-01

    Adaptive nonlinear beamformer technique for analyzing magnetoencephalography (MEG) data has been proved to be powerful tool for both brain research and clinical applications. A general method of analyzing multiple subject data with a formal statistical treatment for the group data has been developed and applied for various types of MEG data. Our latest application of this method was frontal midline theta rhythm (Fmθ), which indicates focused attention and appears widely distributed over medial prefrontal areas in EEG recordings. To localize cortical generators of the magnetic counterpart of Fmθ precisely and identify cortical sources and underlying neural activity associated with mental calculation processing (i.e., arithmetic subtraction), we applied adaptive nonlinear beamformer and permutation analysis on MEG data. As a result, it was indicated that Fmθ is generated in the dorsal anterior cingulate and adjacent medial prefrontal cortex. Gamma event-related synchronization is as an index of activation in right parietal regions subserving mental subtraction associated with basic numerical processing and number-based spatial attention. Gamma desynchronization appeared in the right lateral prefrontal cortex, likely representing a mechanism to interrupt neural activity that can interfere with the ongoing cognitive task. We suggest that the combination of adaptive nonlinear beamformer and permutation analysis on MEG data is quite powerful tool to reveal the oscillatory neuronal dynamics in human brain. PMID:24110810

  14. Wilderness Emergency: Surviving the Unexpected.

    ERIC Educational Resources Information Center

    Fear, Gene

    In any unexpected survival experience, one must accept the situation with just what one has at the moment it happens, where it happens, and how it happens. Problem solving must be based on known body enemies that threaten life, their priority of influence, and their severity of threat to life. Solutions will depend on the body's energy supply,…

  15. Unexpected Outcomes from Teachers' TV

    ERIC Educational Resources Information Center

    Tanner, Ruth

    2006-01-01

    In this article, the author explains why she has unexpectedly become a fan of Teacher's TV. It started when she was asked to show some clips from Teachers' TV as part of a workshop she was leading. She dutifully accepted a CD containing three downloaded programmes about using ICT to teach mathematics and put it into her laptop. Within a few…

  16. Functional brain mapping of the macaque related to spatial working memory as revealed by PET.

    PubMed

    Inoue, Masato; Mikami, Akichika; Ando, Ichiro; Tsukada, Hideo

    2004-01-01

    To define the cortical areas that subserve spatial working memory in a nonhuman primate, we measured regional cerebral blood flow (rCBF) with [(15)O]H(2)O and positron emission tomography while monkeys performed a visually guided saccade (VGS) task and an oculomotor delayed-response (ODR) task. Both Statistical Parametric Mapping and regions of interest-based analyses revealed an increase of rCBF in the area surrounding the principal sulcus (PS), the superior convexity, the anterior bank of the arcuate sulcus (AS), the lateral orbitofrontal cortex (lOFC), the frontal pole (FP), the anterior cingulate cortex (ACC), the lateral bank of the intraparietal sulcus (lIPS) and the prestriate cortex. In the prefrontal cortex (PS, superior convexity, AS, lOFC and FP), rCBF values correlated positively with ODR task performance scores. From the hippocampus, rCBF values correlated negatively with ODR task performance. From the AS, superior convexity, lOFC, FP, ACC and lIPS, rCBF values of the PS correlated positively with rCBF values and negatively with hippocampus rCBF values. These results suggest that neural circuitry in the prefrontal cortex directly contributes the spatial working memory processes and that, in spatial working memory processes, the posterior parietal cortex and hippocampus have a different role to the prefrontal cortex. PMID:14654462

  17. Automatic processing of grammar in the human brain as revealed by the mismatch negativity.

    PubMed

    Pulvermüller, Friedemann; Shtyrov, Yury

    2003-09-01

    The Mismatch Negativity (MMN), a neurophysiological indicator of cognitive processing, was used to investigate grammatical processes in the absence of focused attention to language. Subjects instructed to watch a silent video film and to ignore speech stimuli heard grammatical and ungrammatical spoken word strings that were physically identical up to a divergence point where they differed between each other by a minimal acoustic event, the presence or the absence of a final -s sound. The sentence we come was presented as a rare deviant stimulus against the background of frequently occurring ungrammatical strings, and, in a different experiment, the ungrammatical string *we comes was the deviant in the reverse design. To control for effects related to differences between the critical words, come and comes, control conditions were used in which the same words were presented out of linguistic context. At 100-150 ms after the divergence point, the ungrammatical deviant stimulus elicited a larger MMN than the correct sentence at left-anterior recording sites. This difference was not seen under the out-of-context conditions. In the time range 100-400 ms after stimulus divergence, a spatiotemporal pattern of grammatically related effects was documented by statistically significant interactions of the word and context variables. Minimum-Norm Current Estimates of the cortical sources of the grammaticality effects revealed a main source in the left frontal cortex. We use a neurobiological model of serial order processing to provide a tentative explanation for the data. PMID:14527578

  18. Unexpected bismuth concentration profiles in metal-organic vapor phase epitaxy-grown Ga(As{sub 1−x}Bi{sub x})/GaAs superlattices revealed by Z-contrast scanning transmission electron microscopy imaging

    SciTech Connect

    Wood, A. W.; Babcock, S. E.; Guan, Y.; Forghani, K.; Anand, A.; Kuech, T. F.

    2015-03-01

    A set of GaAs{sub 1−x}Bi{sub x}/GaAs multilayer quantum-well structures was deposited by metal-organic vapor phase epitaxy at 390 °C and 420 °C. The precursor fluxes were introduced with the intent of growing discrete and compositionally uniform GaAs{sub 1−x}Bi{sub x} well and GaAs barrier layers in the epitaxial films. High-resolution high-angle annular-dark-field (or “Z-contrast”) scanning transmission electron microscopy imaging revealed concentration profiles that were periodic in the growth direction, but far more complicated in shape than the intended square wave. The observed composition profiles could explain various reports of physical properties measurements that suggest compositional inhomogeneity in GaAs{sub 1−x}Bi{sub x} alloys as they currently are grown.

  19. Diminished social reward anticipation in the broad autism phenotype as revealed by event-related brain potentials.

    PubMed

    Cox, Anthony; Kohls, Gregor; Naples, Adam J; Mukerji, Cora E; Coffman, Marika C; Rutherford, Helena J V; Mayes, Linda C; McPartland, James C

    2015-10-01

    Diminished responsivity to reward incentives is a key contributor to the social-communication problems seen in autism spectrum disorders (ASDs). Social motivation theories suggest that individuals with ASD do not experience social interactions as rewarding, leading to negative consequences for the development of brain circuitry subserving social information. In this study, we examined neural responses to social and non-social reward anticipation in 35 typically developing young adults, examining modulation of reward sensitivity by level of autistic traits. Using an Event-related potential incentive-delay task incorporating novel, more ecologically valid forms of reward, higher expression of autistic traits was associated with an attenuated P3 response to the anticipation of social (simulated real-time video feedback from an observer), but not non-social (candy), rewards. Exploratory analyses revealed that this was unrelated to mentalizing ability. The P3 component reflects motivated attention to reward signals, suggesting attenuated motivation allocation specific to social incentives. The study extends prior findings of atypical reward anticipation in ASD, demonstrating that attenuated social reward responsiveness extends to autistic traits in the range of typical functioning. Results support the development of innovative paradigms for investigating social and non-social reward responsiveness. Insight into vulnerabilities in reward processing is critical for understanding social function in ASD. PMID:25752905

  20. Individual Variability and Test-Retest Reliability Revealed by Ten Repeated Resting-State Brain Scans over One Month.

    PubMed

    Chen, Bing; Xu, Ting; Zhou, Changle; Wang, Luoyu; Yang, Ning; Wang, Ze; Dong, Hao-Ming; Yang, Zhi; Zang, Yu-Feng; Zuo, Xi-Nian; Weng, Xu-Chu

    2015-01-01

    Individual differences in mind and behavior are believed to reflect the functional variability of the human brain. Due to the lack of a large-scale longitudinal dataset, the full landscape of variability within and between individual functional connectomes is largely unknown. We collected 300 resting-state functional magnetic resonance imaging (rfMRI) datasets from 30 healthy participants who were scanned every three days for one month. With these data, both intra- and inter-individual variability of six common rfMRI metrics, as well as their test-retest reliability, were estimated across multiple spatial scales. Global metrics were more dynamic than local regional metrics. Cognitive components involving working memory, inhibition, attention, language and related neural networks exhibited high intra-individual variability. In contrast, inter-individual variability demonstrated a more complex picture across the multiple scales of metrics. Limbic, default, frontoparietal and visual networks and their related cognitive components were more differentiable than somatomotor and attention networks across the participants. Analyzing both intra- and inter-individual variability revealed a set of high-resolution maps on test-retest reliability of the multi-scale connectomic metrics. These findings represent the first collection of individual differences in multi-scale and multi-metric characterization of the human functional connectomes in-vivo, serving as normal references for the field to guide the use of common functional metrics in rfMRI-based applications.

  1. Individual Variability and Test-Retest Reliability Revealed by Ten Repeated Resting-State Brain Scans over One Month

    PubMed Central

    Zhou, Changle; Wang, Luoyu; Yang, Ning; Wang, Ze; Dong, Hao-Ming; Yang, Zhi; Zang, Yu-Feng; Zuo, Xi-Nian; Weng, Xu-Chu

    2015-01-01

    Individual differences in mind and behavior are believed to reflect the functional variability of the human brain. Due to the lack of a large-scale longitudinal dataset, the full landscape of variability within and between individual functional connectomes is largely unknown. We collected 300 resting-state functional magnetic resonance imaging (rfMRI) datasets from 30 healthy participants who were scanned every three days for one month. With these data, both intra- and inter-individual variability of six common rfMRI metrics, as well as their test-retest reliability, were estimated across multiple spatial scales. Global metrics were more dynamic than local regional metrics. Cognitive components involving working memory, inhibition, attention, language and related neural networks exhibited high intra-individual variability. In contrast, inter-individual variability demonstrated a more complex picture across the multiple scales of metrics. Limbic, default, frontoparietal and visual networks and their related cognitive components were more differentiable than somatomotor and attention networks across the participants. Analyzing both intra- and inter-individual variability revealed a set of high-resolution maps on test-retest reliability of the multi-scale connectomic metrics. These findings represent the first collection of individual differences in multi-scale and multi-metric characterization of the human functional connectomes in-vivo, serving as normal references for the field to guide the use of common functional metrics in rfMRI-based applications. PMID:26714192

  2. Tactile Object Familiarity in the Blind Brain Reveals the Supramodal Perceptual-Mnemonic Nature of the Perirhinal Cortex

    PubMed Central

    Cacciamani, Laura; Likova, Lora T.

    2016-01-01

    This study is the first to investigate the neural underpinnings of tactile object familiarity in the blind during both perception and memory. In the sighted, the perirhinal cortex (PRC) has been implicated in the assessment of visual object familiarity—a crucial everyday task—as evidenced by reduced activation when an object becomes familiar. Here, to examine the PRC’s role in tactile object familiarity in the absence of vision, we trained blind participants on a unique memory-guided drawing technique and measured brain activity while they perceptually explored raised-line drawings, drew them from tactile memory, and scribbled (control). Functional magnetic resonance imaging (fMRI) before and after a week of training revealed a significant decrease in PRC activation from pre- to post-training (i.e., from unfamiliar to familiar) during perceptual exploration as well as memory-guided drawing, but not scribbling. This familiarity-based reduction is the first evidence that the PRC represents tactile object familiarity in the blind. Furthermore, the finding of this effect during both tactile perception and tactile memory provides the critical link in establishing the PRC as a structure whose representations are supramodal for both perception and memory. PMID:27148002

  3. Diminished social reward anticipation in the broad autism phenotype as revealed by event-related brain potentials

    PubMed Central

    Cox, Anthony; Kohls, Gregor; Naples, Adam J.; Mukerji, Cora E.; Coffman, Marika C.; Rutherford, Helena J. V.; Mayes, Linda C.

    2015-01-01

    Diminished responsivity to reward incentives is a key contributor to the social-communication problems seen in autism spectrum disorders (ASDs). Social motivation theories suggest that individuals with ASD do not experience social interactions as rewarding, leading to negative consequences for the development of brain circuitry subserving social information. In this study, we examined neural responses to social and non-social reward anticipation in 35 typically developing young adults, examining modulation of reward sensitivity by level of autistic traits. Using an Event-related potential incentive-delay task incorporating novel, more ecologically valid forms of reward, higher expression of autistic traits was associated with an attenuated P3 response to the anticipation of social (simulated real-time video feedback from an observer), but not non-social (candy), rewards. Exploratory analyses revealed that this was unrelated to mentalizing ability. The P3 component reflects motivated attention to reward signals, suggesting attenuated motivation allocation specific to social incentives. The study extends prior findings of atypical reward anticipation in ASD, demonstrating that attenuated social reward responsiveness extends to autistic traits in the range of typical functioning. Results support the development of innovative paradigms for investigating social and non-social reward responsiveness. Insight into vulnerabilities in reward processing is critical for understanding social function in ASD. PMID:25752905

  4. Diminished social reward anticipation in the broad autism phenotype as revealed by event-related brain potentials.

    PubMed

    Cox, Anthony; Kohls, Gregor; Naples, Adam J; Mukerji, Cora E; Coffman, Marika C; Rutherford, Helena J V; Mayes, Linda C; McPartland, James C

    2015-10-01

    Diminished responsivity to reward incentives is a key contributor to the social-communication problems seen in autism spectrum disorders (ASDs). Social motivation theories suggest that individuals with ASD do not experience social interactions as rewarding, leading to negative consequences for the development of brain circuitry subserving social information. In this study, we examined neural responses to social and non-social reward anticipation in 35 typically developing young adults, examining modulation of reward sensitivity by level of autistic traits. Using an Event-related potential incentive-delay task incorporating novel, more ecologically valid forms of reward, higher expression of autistic traits was associated with an attenuated P3 response to the anticipation of social (simulated real-time video feedback from an observer), but not non-social (candy), rewards. Exploratory analyses revealed that this was unrelated to mentalizing ability. The P3 component reflects motivated attention to reward signals, suggesting attenuated motivation allocation specific to social incentives. The study extends prior findings of atypical reward anticipation in ASD, demonstrating that attenuated social reward responsiveness extends to autistic traits in the range of typical functioning. Results support the development of innovative paradigms for investigating social and non-social reward responsiveness. Insight into vulnerabilities in reward processing is critical for understanding social function in ASD.

  5. Event-related brain potentials reveal correlates of the transformation of stimulus functions through derived relations in healthy humans.

    PubMed

    O'Regan, L M; Farina, F R; Hussey, I; Roche, R A P

    2015-03-01

    This research aimed to explore the neural correlates of relational learning by recording high-density EEG during a behavioural task involving derivation levels of varying complexity. A total of 15 participants (5 male; age range 18-23 years; mean age=20.0 years) completed contextual cue training, relational learning, function training and a derivation task while 128-channel event-related potentials (ERPs) were recorded from the scalp (Background). Differences in response latencies were observed between the two derived (symmetry and equivalence) and directly trained relations, with longest latencies found for equivalence and shortest for the directly trained relations. This pattern failed to reach statistical significance. Importantly, ERPs revealed an early P3a positivity (from 230 to 350ms) over right posterior scalp sites. Significantly larger mean amplitudes were found at three channels (P6, E115 and E121) for the equivalence relations compared to the two other types (Results). We believe this may constitute a first demonstration of differences in brain electrophysiology in the transformation of stimulus functions through derived relations of hierarchical levels of complexity (Conclusions).

  6. Three-dimensional brain atlas of pygmy squid, Idiosepius paradoxus, revealing the largest relative vertical lobe system volume among the cephalopods.

    PubMed

    Koizumi, Motoki; Shigeno, Shuichi; Mizunami, Makoto; Tanaka, Nobuaki K

    2016-07-01

    Cephalopods have the largest and most complex nervous system of all invertebrates, and the brain-to-body weight ratio exceeds those of most fish and reptiles. The brain is composed of lobe units, the functions of which have been studied through surgical manipulation and electrical stimulation. However, how information is processed in each lobe for the animal to make a behavioral decision has rarely been investigated. To perform such functional analyses, it is necessary to precisely describe how brain lobes are spatially organized and mutually interconnected as a whole. We thus made three-dimensional digital brain atlases of both hatchling and juvenile pygmy squid, Idiosepius paradoxus. I. paradoxus is the smallest squid and has a brain small enough to scan as a whole region in the field-of-view of a low-magnification laser scan microscope objective. Precise analyses of the confocal images of the brains revealed one newly identified lobe and also that the relative volume of the vertical lobe system, the higher association center, in the pygmy squid represents the largest portion compared with the cephalopod species reported previously. In addition, principal component analyses of relative volumes of lobe complexes revealed that the organization of I. paradoxus brain is comparable to those of Decapodiformes species commonly used to analyze complex behaviors such as Sepia officinalis and Sepioteuthis sepioidea. These results suggest that the pygmy squid can be a good model to investigate the brain functions of coleoids utilizing physiological methods. J. Comp. Neurol. 524:2142-2157, 2016. © 2016 Wiley Periodicals, Inc. PMID:26663197

  7. Analysis of tumour- and stroma-supplied proteolytic networks reveals a brain-metastasis-promoting role for cathepsin S.

    PubMed

    Sevenich, Lisa; Bowman, Robert L; Mason, Steven D; Quail, Daniela F; Rapaport, Franck; Elie, Benelita T; Brogi, Edi; Brastianos, Priscilla K; Hahn, William C; Holsinger, Leslie J; Massagué, Joan; Leslie, Christina S; Joyce, Johanna A

    2014-09-01

    Metastasis remains the most common cause of death in most cancers, with limited therapies for combating disseminated disease. While the primary tumour microenvironment is an important regulator of cancer progression, it is less well understood how different tissue environments influence metastasis. We analysed tumour-stroma interactions that modulate organ tropism of brain, bone and lung metastasis in xenograft models. We identified a number of potential modulators of site-specific metastasis, including cathepsin S as a regulator of breast-to-brain metastasis. High cathepsin S expression at the primary site correlated with decreased brain metastasis-free survival in breast cancer patients. Both macrophages and tumour cells produce cathepsin S, and only the combined depletion significantly reduced brain metastasis in vivo. Cathepsin S specifically mediates blood-brain barrier transmigration through proteolytic processing of the junctional adhesion molecule, JAM-B. Pharmacological inhibition of cathepsin S significantly reduced experimental brain metastasis, supporting its consideration as a therapeutic target for this disease.

  8. Multichannel brain recordings in behaving Drosophila reveal oscillatory activity and local coherence in response to sensory stimulation and circuit activation

    PubMed Central

    Paulk, Angelique C.; Zhou, Yanqiong; Stratton, Peter; Liu, Li

    2013-01-01

    Neural networks in vertebrates exhibit endogenous oscillations that have been associated with functions ranging from sensory processing to locomotion. It remains unclear whether oscillations may play a similar role in the insect brain. We describe a novel “whole brain” readout for Drosophila melanogaster using a simple multichannel recording preparation to study electrical activity across the brain of flies exposed to different sensory stimuli. We recorded local field potential (LFP) activity from >2,000 registered recording sites across the fly brain in >200 wild-type and transgenic animals to uncover specific LFP frequency bands that correlate with: 1) brain region; 2) sensory modality (olfactory, visual, or mechanosensory); and 3) activity in specific neural circuits. We found endogenous and stimulus-specific oscillations throughout the fly brain. Central (higher-order) brain regions exhibited sensory modality-specific increases in power within narrow frequency bands. Conversely, in sensory brain regions such as the optic or antennal lobes, LFP coherence, rather than power, best defined sensory responses across modalities. By transiently activating specific circuits via expression of TrpA1, we found that several circuits in the fly brain modulate LFP power and coherence across brain regions and frequency domains. However, activation of a neuromodulatory octopaminergic circuit specifically increased neuronal coherence in the optic lobes during visual stimulation while decreasing coherence in central brain regions. Our multichannel recording and brain registration approach provides an effective way to track activity simultaneously across the fly brain in vivo, allowing investigation of functional roles for oscillations in processing sensory stimuli and modulating behavior. PMID:23864378

  9. Lazarillo expression reveals a subset of neurons contributing to the primary axon scaffold of the embryonic brain of the grasshopper Schistocerca gregaria.

    PubMed

    Graf, S; Ludwig, P; Boyan, G

    2000-04-10

    The authors studied the contribution of seven clusters of Lazarillo-expressing cells to the primary axon scaffold of the brain in the grasshopper Schistocerca gregaria from 26% to 43% of embryogenesis. Each cluster, which was numbered according to when Lazarillo expression first appeared, was uniquely identifiable on the basis of its stereotypic position in the brain and the number of Lazarillo-expressing cells it contained. At no time during embryogenesis was Lazarillo expression found in brain neuroblasts: It was found only in progeny. For ease of analysis, axogenesis was followed in a cell cluster that contained only a single Lazarillo-expressing cell (the lateral cell) in the dorsal median domain of the brain midline. Bromodeoxyuridine incorporation revealed the presence of only a single midline precursor cell in this region during embryogenesis. Intracellular injection of Lucifer yellow into the lateral cell at various ages showed that there was no dye coupling to the midline precursor or to the nearby term-1-expressing primary commissure pioneers. The lateral cell is not related lineally to these cells and most likely differentiates directly from the neuroectoderm of the brain midline. Lazarillo expression appears at the onset of axogenesis as the lateral cell projects an axon laterally toward the next Lazarillo-expressing cell cluster. The cells of this target cluster direct axons into separate brain regions, thereby establishing an orthogonally organized scaffold that the lateral cell axon follows as it navigates away from the brain midline. The primary axon scaffold of the brain results from a stepwise interlinking of discrete brain regions, as exemplified by axons from neighboring Lazarillo-expressing cell clusters.

  10. Unexpected and sudden death due to undiagnosed medulloblastoma in twin pregnancy: A case report.

    PubMed

    Ventura, Francesco; Barranco, Rosario; Gentile, Raffaella; Vergani, Patrizia

    2016-09-01

    The authors describe an unusual case of sudden and unexpected death caused by a medulloblastoma in a woman aged 28, native of South America, at the 33rd week of twin pregnancy, with neurological signs appeared a month before death. The initial symptoms were attributed to epiphenomena of pregnancy. Two weeks after hospitalization, the woman showed an acute frontal headache that prevented movement and caused a rapid lowering of arterial oxygen saturation. The patient died around 3h later, despite resuscitation. Immediately after, a caesarean section was performed but it was not enough to prevent the death of the two foetuses. The autopsy revealed the presence of a tumour between the left lobe of the cerebellum and the vermis. Histological examination enabled to identify a medulloblastoma. Death was attributed to acute cardio-respiratory insufficiency caused by compression of the brain stem. Foetuses showed no malformation and their death was due to an acute hypoxia resulting from the mother cardiovascular arrest. PMID:27595435

  11. Unexpected and sudden death due to undiagnosed medulloblastoma in twin pregnancy: A case report.

    PubMed

    Ventura, Francesco; Barranco, Rosario; Gentile, Raffaella; Vergani, Patrizia

    2016-09-01

    The authors describe an unusual case of sudden and unexpected death caused by a medulloblastoma in a woman aged 28, native of South America, at the 33rd week of twin pregnancy, with neurological signs appeared a month before death. The initial symptoms were attributed to epiphenomena of pregnancy. Two weeks after hospitalization, the woman showed an acute frontal headache that prevented movement and caused a rapid lowering of arterial oxygen saturation. The patient died around 3h later, despite resuscitation. Immediately after, a caesarean section was performed but it was not enough to prevent the death of the two foetuses. The autopsy revealed the presence of a tumour between the left lobe of the cerebellum and the vermis. Histological examination enabled to identify a medulloblastoma. Death was attributed to acute cardio-respiratory insufficiency caused by compression of the brain stem. Foetuses showed no malformation and their death was due to an acute hypoxia resulting from the mother cardiovascular arrest.

  12. Senile plaques and other senile changes in the brain of an aged American black bear.

    PubMed

    Uchida, K; Yoshino, T; Yamaguchi, R; Tateyama, S; Kimoto, Y; Nakayama, H; Goto, N

    1995-07-01

    A female American black bear (Euarctos ursus americanus) over 20 years old had shown epileptiform neurologic signs starting in March 1992 and was found dead unexpectedly 8 months later. At necropsy, pulmonary and intrabronchial hemorrhage was noted. In the brain, the leptomeninges exhibited slight thickening, and petechiae were evident in the hippocampus. Histopathologic examination of the brain revealed several senile changes: numerous senile plaques, amyloid deposition in cerebromeningeal arterioles, mineral deposition in the pallidum, and numerous corpora amylacea in the cerebellum. PMID:7483216

  13. Proton Magnetic Resonance Spectroscopy and MRI Reveal No Evidence for Brain Mitochondrial Dysfunction in Children with Autism Spectrum Disorder

    ERIC Educational Resources Information Center

    Corrigan, Neva M.; Shaw, Dennis. W. W.; Richards, Todd L.; Estes, Annette M.; Friedman, Seth D.; Petropoulos, Helen; Artru, Alan A.; Dager, Stephen R.

    2012-01-01

    Brain mitochondrial dysfunction has been proposed as an etiologic factor in autism spectrum disorder (ASD). Proton magnetic resonance spectroscopic imaging ([superscript 1]HMRS) and MRI were used to assess for evidence of brain mitochondrial dysfunction in longitudinal samples of children with ASD or developmental delay (DD), and cross-sectionally…

  14. Organization and evolution of brain lipidome revealed by large-scale analysis of human, chimpanzee, macaque, and mouse tissues.

    PubMed

    Bozek, Katarzyna; Wei, Yuning; Yan, Zheng; Liu, Xiling; Xiong, Jieyi; Sugimoto, Masahiro; Tomita, Masaru; Pääbo, Svante; Sherwood, Chet C; Hof, Patrick R; Ely, John J; Li, Yan; Steinhauser, Dirk; Willmitzer, Lothar; Giavalisco, Patrick; Khaitovich, Philipp

    2015-02-18

    Lipids are prominent components of the nervous system. Here we performed a large-scale mass spectrometry-based analysis of the lipid composition of three brain regions as well as kidney and skeletal muscle of humans, chimpanzees, rhesus macaques, and mice. The human brain shows the most distinct lipid composition: 76% of 5,713 lipid compounds examined in our study are either enriched or depleted in the human brain. Concentration levels of lipids enriched in the brain evolve approximately four times faster among primates compared with lipids characteristic of non-neural tissues and show further acceleration of change in human neocortical regions but not in the cerebellum. Human-specific concentration changes are supported by human-specific expression changes for corresponding enzymes. These results provide the first insights into the role of lipids in human brain evolution.

  15. Organization and evolution of brain lipidome revealed by large-scale analysis of human, chimpanzee, macaque, and mouse tissues.

    PubMed

    Bozek, Katarzyna; Wei, Yuning; Yan, Zheng; Liu, Xiling; Xiong, Jieyi; Sugimoto, Masahiro; Tomita, Masaru; Pääbo, Svante; Sherwood, Chet C; Hof, Patrick R; Ely, John J; Li, Yan; Steinhauser, Dirk; Willmitzer, Lothar; Giavalisco, Patrick; Khaitovich, Philipp

    2015-02-18

    Lipids are prominent components of the nervous system. Here we performed a large-scale mass spectrometry-based analysis of the lipid composition of three brain regions as well as kidney and skeletal muscle of humans, chimpanzees, rhesus macaques, and mice. The human brain shows the most distinct lipid composition: 76% of 5,713 lipid compounds examined in our study are either enriched or depleted in the human brain. Concentration levels of lipids enriched in the brain evolve approximately four times faster among primates compared with lipids characteristic of non-neural tissues and show further acceleration of change in human neocortical regions but not in the cerebellum. Human-specific concentration changes are supported by human-specific expression changes for corresponding enzymes. These results provide the first insights into the role of lipids in human brain evolution. PMID:25661180

  16. Altered Spontaneous Brain Activity in Patients with Acute Spinal Cord Injury Revealed by Resting-State Functional MRI

    PubMed Central

    Zhu, Ling; Wu, Guangyao; Zhou, Xin; Li, Jielan; Wen, Zhi; Lin, Fuchun

    2015-01-01

    Background Previous neuroimaging studies have provided evidence of structural and functional reorganization of brain in patients with chronic spinal cord injury (SCI). However, it remains unknown whether the spontaneous brain activity changes in acute SCI. In this study, we investigated intrinsic brain activity in acute SCI patients using a regional homogeneity (ReHo) analysis based on resting-state functional magnetic resonance imaging. Methods A total of 15 patients with acute SCI and 16 healthy controls participated in the study. The ReHo value was used to evaluate spontaneous brain activity, and voxel-wise comparisons of ReHo were performed to identify brain regions with altered spontaneous brain activity between groups. We also assessed the associations between ReHo and the clinical scores in brain regions showing changed spontaneous brain activity. Results Compared with the controls, the acute SCI patients showed decreased ReHo in the bilateral primary motor cortex/primary somatosensory cortex, bilateral supplementary motor area/dorsal lateral prefrontal cortex, right inferior frontal gyrus, bilateral dorsal anterior cingulate cortex and bilateral caudate; and increased ReHo in bilateral precuneus, the left inferior parietal lobe, the left brainstem/hippocampus, the left cingulate motor area, bilateral insula, bilateral thalamus and bilateral cerebellum. The average ReHo values of the left thalamus and right insula were negatively correlated with the international standards for the neurological classification of spinal cord injury motor scores. Conclusion Our findings indicate that acute distant neuronal damage has an immediate impact on spontaneous brain activity. In acute SCI patients, the ReHo was prominently altered in brain regions involved in motor execution and cognitive control, default mode network, and which are associated with sensorimotor compensatory reorganization. Abnormal ReHo values in the left thalamus and right insula could serve as

  17. Connectivity-based whole brain dual parcellation by group ICA reveals tract structures and decreased connectivity in schizophrenia.

    PubMed

    Wu, Lei; Calhoun, Vince D; Jung, Rex E; Caprihan, Arvind

    2015-11-01

    Mapping brain connectivity based on neuroimaging data is a promising new tool for understanding brain structure and function. In this methods paper, we demonstrate that group independent component analysis (GICA) can be used to perform a dual parcellation of the brain based on its connectivity matrix (cmICA). This dual parcellation consists of a set of spatially independent source maps, and a corresponding set of paired dual maps that define the connectivity of each source map to the brain. These dual maps are called the connectivity profiles of the source maps. Traditional analysis of connectivity matrices has been used previously for brain parcellation, but the present method provides additional information on the connectivity of these segmented regions. In this paper, the whole brain structural connectivity matrices were calculated on a 5 mm(3) voxel scale from diffusion imaging data based on the probabilistic tractography method. The effect of the choice of the number of components (30 and 100) and their stability were examined. This method generated a set of spatially independent components that are consistent with the canonical brain tracts provided by previous anatomic descriptions, with the high order model yielding finer segmentations. The corpus-callosum example shows how this method leads to a robust parcellation of a brain structure based on its connectivity properties. We applied cmICA to study structural connectivity differences between a group of schizophrenia subjects and healthy controls. The connectivity profiles at both model orders showed similar regions with reduced connectivity in schizophrenia patients. These regions included forceps major, right inferior fronto-occipital fasciculus, uncinate fasciculus, thalamic radiation, and corticospinal tract. This paper provides a novel unsupervised data-driven framework that summarizes the information in a large global connectivity matrix and tests for brain connectivity differences. It has the

  18. Noninvasive monitoring of treatment response in a rabbit cyanide toxicity model reveals differences in brain and muscle metabolism.

    PubMed

    Kim, Jae G; Lee, Jangwoen; Mahon, Sari B; Mukai, David; Patterson, Steven E; Boss, Gerry R; Tromberg, Bruce J; Brenner, Matthew

    2012-10-01

    Noninvasive near infrared spectroscopy measurements were performed to monitor cyanide (CN) poisoning and recovery in the brain region and in foreleg muscle simultaneously, and the effects of a novel CN antidote, sulfanegen sodium, on tissue hemoglobin oxygenation changes were compared using a sub-lethal rabbit model. The results demonstrated that the brain region is more susceptible to CN poisoning and slower in endogenous CN detoxification following exposure than peripheral muscles. However, sulfanegen sodium rapidly reversed CN toxicity, with brain region effects reversing more quickly than muscle. In vivo monitoring of multiple organs may provide important clinical information regarding the extent of CN toxicity and subsequent recovery, and facilitate antidote drug development.

  19. Noninvasive monitoring of treatment response in a rabbit cyanide toxicity model reveals differences in brain and muscle metabolism

    NASA Astrophysics Data System (ADS)

    Kim, Jae G.; Lee, Jangwoen; Mahon, Sari B.; Mukai, David; Patterson, Steven E.; Boss, Gerry R.; Tromberg, Bruce J.; Brenner, Matthew

    2012-10-01

    Noninvasive near infrared spectroscopy measurements were performed to monitor cyanide (CN) poisoning and recovery in the brain region and in foreleg muscle simultaneously, and the effects of a novel CN antidote, sulfanegen sodium, on tissue hemoglobin oxygenation changes were compared using a sub-lethal rabbit model. The results demonstrated that the brain region is more susceptible to CN poisoning and slower in endogenous CN detoxification following exposure than peripheral muscles. However, sulfanegen sodium rapidly reversed CN toxicity, with brain region effects reversing more quickly than muscle. In vivo monitoring of multiple organs may provide important clinical information regarding the extent of CN toxicity and subsequent recovery, and facilitate antidote drug development.

  20. Water in stars: expected and unexpected

    NASA Astrophysics Data System (ADS)

    Tsuji, T.; Aoki, W.; Ohnaka, K.

    1999-03-01

    We have confirmed the presence of water in the early M giant α Cet (M1.5III) and supergiant KK Per (M2Iab) by the highest resolution grating mode of SWS, but this result is quite unexpected from present model atmospheres. In late M giant and supergiant stars, water observed originates partly in the photosphere as expected by the model atmospheres, but ISO SWS has revealed that the 2.7 mic\\ absorption bands appear to be somewhat stronger than predicted while 6.5 mic\\ bands weaker, indicating the contamination by an emission component. In the mid-infrared region extending to 45 mic, pure rotation lines of hho\\ appear as distinct emission on the high resolution SWS spectra of 30g Her (M7III) and S Per (M4-7Ia), along with the dust emission at 10, 13, 20 mic\\ and a new unidentified feature at 30 mic. Thus, together with the dust, water contributes to the thermal balance of the outer atmosphere already in the mid-infrared. The excitation temperature of hho\\ gas is estimated to be 500 - 1000 K. In view of this result for late M (super)giants, unexpected water observed in early M (super)giants should also be of non-photospheric in origin. Thus, ISO has finally established the presence of a new component of the outer atmosphere - a warm molecular envelope - in red giant and supergiant stars from early to late types. Such a rather warm molecular envelope will be a site of various activities such as chemical reactions, dust formation, mass-outflow etc.

  1. Single muscle fiber proteomics reveals unexpected mitochondrial specialization

    PubMed Central

    Murgia, Marta; Nagaraj, Nagarjuna; Deshmukh, Atul S; Zeiler, Marlis; Cancellara, Pasqua; Moretti, Irene; Reggiani, Carlo; Schiaffino, Stefano; Mann, Matthias

    2015-01-01

    Mammalian skeletal muscles are composed of multinucleated cells termed slow or fast fibers according to their contractile and metabolic properties. Here, we developed a high-sensitivity workflow to characterize the proteome of single fibers. Analysis of segments of the same fiber by traditional and unbiased proteomics methods yielded the same subtype assignment. We discovered novel subtype-specific features, most prominently mitochondrial specialization of fiber types in substrate utilization. The fiber type-resolved proteomes can be applied to a variety of physiological and pathological conditions and illustrate the utility of single cell type analysis for dissecting proteomic heterogeneity. PMID:25643707

  2. Natural Minor Scale is More Natural to the Brain than Harmonic Minor Scale as Revealed by Magnetoencephalography

    NASA Astrophysics Data System (ADS)

    Ando, Hiromitsu; Nemoto, Iku; Oda, Shoichiro

    Minor mode is known to elicit stronger emotional responses than major mode in the brain. The present work focused on the minor scales and natural and harmonic minor scales were compared in automatic brain responses in an oddball paradigm. The standard stimulus was either the natural or harmonic minor scale, and a deviant stimulus lacked one scale tone of the corresponding complete minor scale. The brain responded to omission of every tone but omission of the tone B flat in the natural minor experiment elicited larger response than that of the other tones. In particular, the response was significantly larger than that to omission of B in the harmonic minor experiment. This result suggested that the brain felt the natural minor scale to be actually more natural than the harmonic minor scale.

  3. Our Faces in the Dog's Brain: Functional Imaging Reveals Temporal Cortex Activation during Perception of Human Faces.

    PubMed

    Cuaya, Laura V; Hernández-Pérez, Raúl; Concha, Luis

    2016-01-01

    Dogs have a rich social relationship with humans. One fundamental aspect of it is how dogs pay close attention to human faces in order to guide their behavior, for example, by recognizing their owner and his/her emotional state using visual cues. It is well known that humans have specific brain regions for the processing of other human faces, yet it is unclear how dogs' brains process human faces. For this reason, our study focuses on describing the brain correlates of perception of human faces in dogs using functional magnetic resonance imaging (fMRI). We trained seven domestic dogs to remain awake, still and unrestrained inside an MRI scanner. We used a visual stimulation paradigm with block design to compare activity elicited by human faces against everyday objects. Brain activity related to the perception of faces changed significantly in several brain regions, but mainly in the bilateral temporal cortex. The opposite contrast (i.e., everyday objects against human faces) showed no significant brain activity change. The temporal cortex is part of the ventral visual pathway, and our results are consistent with reports in other species like primates and sheep, that suggest a high degree of evolutionary conservation of this pathway for face processing. This study introduces the temporal cortex as candidate to process human faces, a pillar of social cognition in dogs.

  4. Connectivity profiles reveal the relationship between brain areas for social cognition in human and monkey temporoparietal cortex.

    PubMed

    Mars, Rogier B; Sallet, Jérôme; Neubert, Franz-Xaver; Rushworth, Matthew F S

    2013-06-25

    The human ability to infer the thoughts and beliefs of others, often referred to as "theory of mind," as well as the predisposition to even consider others, are associated with activity in the temporoparietal junction (TPJ) area. Unlike the case of most human brain areas, we have little sense of whether or how TPJ is related to brain areas in other nonhuman primates. It is not possible to address this question by looking for similar task-related activations in nonhuman primates because there is no evidence that nonhuman primates engage in theory-of-mind tasks in the same manner as humans. Here, instead, we explore the relationship by searching for areas in the macaque brain that interact with other macaque brain regions in the same manner as human TPJ interacts with other human brain regions. In other words, we look for brain regions with similar positions within a distributed neural circuit in the two species. We exploited the fact that human TPJ has a unique functional connectivity profile with cortical areas with known homologs in the macaque. For each voxel in the macaque temporal and parietal cortex we evaluated the similarity of its functional connectivity profile to that of human TPJ. We found that areas in the middle part of the superior temporal cortex, often associated with the processing of faces and other social stimuli, have the most similar connectivity profile. These results suggest that macaque face processing areas and human mentalizing areas might have a similar precursor.

  5. Our Faces in the Dog's Brain: Functional Imaging Reveals Temporal Cortex Activation during Perception of Human Faces.

    PubMed

    Cuaya, Laura V; Hernández-Pérez, Raúl; Concha, Luis

    2016-01-01

    Dogs have a rich social relationship with humans. One fundamental aspect of it is how dogs pay close attention to human faces in order to guide their behavior, for example, by recognizing their owner and his/her emotional state using visual cues. It is well known that humans have specific brain regions for the processing of other human faces, yet it is unclear how dogs' brains process human faces. For this reason, our study focuses on describing the brain correlates of perception of human faces in dogs using functional magnetic resonance imaging (fMRI). We trained seven domestic dogs to remain awake, still and unrestrained inside an MRI scanner. We used a visual stimulation paradigm with block design to compare activity elicited by human faces against everyday objects. Brain activity related to the perception of faces changed significantly in several brain regions, but mainly in the bilateral temporal cortex. The opposite contrast (i.e., everyday objects against human faces) showed no significant brain activity change. The temporal cortex is part of the ventral visual pathway, and our results are consistent with reports in other species like primates and sheep, that suggest a high degree of evolutionary conservation of this pathway for face processing. This study introduces the temporal cortex as candidate to process human faces, a pillar of social cognition in dogs. PMID:26934715

  6. Our Faces in the Dog's Brain: Functional Imaging Reveals Temporal Cortex Activation during Perception of Human Faces

    PubMed Central

    Cuaya, Laura V.; Hernández-Pérez, Raúl; Concha, Luis

    2016-01-01

    Dogs have a rich social relationship with humans. One fundamental aspect of it is how dogs pay close attention to human faces in order to guide their behavior, for example, by recognizing their owner and his/her emotional state using visual cues. It is well known that humans have specific brain regions for the processing of other human faces, yet it is unclear how dogs’ brains process human faces. For this reason, our study focuses on describing the brain correlates of perception of human faces in dogs using functional magnetic resonance imaging (fMRI). We trained seven domestic dogs to remain awake, still and unrestrained inside an MRI scanner. We used a visual stimulation paradigm with block design to compare activity elicited by human faces against everyday objects. Brain activity related to the perception of faces changed significantly in several brain regions, but mainly in the bilateral temporal cortex. The opposite contrast (i.e., everyday objects against human faces) showed no significant brain activity change. The temporal cortex is part of the ventral visual pathway, and our results are consistent with reports in other species like primates and sheep, that suggest a high degree of evolutionary conservation of this pathway for face processing. This study introduces the temporal cortex as candidate to process human faces, a pillar of social cognition in dogs. PMID:26934715

  7. Altered spontaneous brain activity in patients with Parkinson's disease accompanied by depressive symptoms, as revealed by regional homogeneity and functional connectivity in the prefrontal-limbic system.

    PubMed

    Sheng, Ke; Fang, Weidong; Su, Meilan; Li, Rong; Zou, Dezhi; Han, Yu; Wang, Xuefeng; Cheng, Oumei

    2014-01-01

    As patients with Parkinson's disease (PD) are at high risk for comorbid depression, it is hypothesized that these two diseases are sharing common pathogenic pathways. Using regional homogeneity (ReHo) and functional connectivity approaches, we characterized human regional brain activity at resting state to examine specific brain networks in patients with PD and those with PD and depression (PDD). This study comprised 41 PD human patients and 25 normal human subjects. The patients completed the Hamilton Depression Rating Scale and were further divided into two groups: patients with depressive symptoms and non-depressed PD patients (nD-PD). Compared with the non-depressed patients, those with depressive symptoms exhibited significantly increased regional activity in the left middle frontal gyrus and right inferior frontal gyrus, and decreased ReHo in the left amygdala and bilateral lingual gyrus. Brain network connectivity analysis revealed decreased functional connectivity within the prefrontal-limbic system and increased functional connectivity in the prefrontal cortex and lingual gyrus in PDD compared with the nD-PD group. In summary, the findings showed regional brain activity alterations and disruption of the mood regulation network in PDD patients. The pathogenesis of PDD may be attributed to abnormal neural activity in multiple brain regions.

  8. Whole-brain, time-locked activation with simple tasks revealed using massive averaging and model-free analysis

    PubMed Central

    Gonzalez-Castillo, Javier; Saad, Ziad S.; Handwerker, Daniel A.; Inati, Souheil J.; Brenowitz, Noah; Bandettini, Peter A.

    2012-01-01

    The brain is the body's largest energy consumer, even in the absence of demanding tasks. Electrophysiologists report on-going neuronal firing during stimulation or task in regions beyond those of primary relationship to the perturbation. Although the biological origin of consciousness remains elusive, it is argued that it emerges from complex, continuous whole-brain neuronal collaboration. Despite converging evidence suggesting the whole brain is continuously working and adapting to anticipate and actuate in response to the environment, over the last 20 y, task-based functional MRI (fMRI) have emphasized a localizationist view of brain function, with fMRI showing only a handful of activated regions in response to task/stimulation. Here, we challenge that view with evidence that under optimal noise conditions, fMRI activations extend well beyond areas of primary relationship to the task; and blood-oxygen level-dependent signal changes correlated with task-timing appear in over 95% of the brain for a simple visual stimulation plus attention control task. Moreover, we show that response shape varies substantially across regions, and that whole-brain parcellations based on those differences produce distributed clusters that are anatomically and functionally meaningful, symmetrical across hemispheres, and reproducible across subjects. These findings highlight the exquisite detail lying in fMRI signals beyond what is normally examined, and emphasize both the pervasiveness of false negatives, and how the sparseness of fMRI maps is not a result of localized brain function, but a consequence of high noise and overly strict predictive response models. PMID:22431587

  9. Voxel-based morphometry analysis reveals frontal brain differences in participants with ADHD and their unaffected siblings

    PubMed Central

    Bralten, Janita; Greven, Corina U.; Franke, Barbara; Mennes, Maarten; Zwiers, Marcel P.; Rommelse, Nanda N.J.; Hartman, Catharina; van der Meer, Dennis; O’Dwyer, Laurence; Oosterlaan, Jaap; Hoekstra, Pieter J.; Heslenfeld, Dirk; Arias-Vasquez, Alejandro; Buitelaar, Jan K.

    2016-01-01

    Background Data on structural brain alterations in patients with attention-deficit/hyperactivity disorder (ADHD) have been inconsistent. Both ADHD and brain volumes have a strong genetic loading, but whether brain alterations in patients with ADHD are familial has been underexplored. We aimed to detect structural brain alterations in adolescents and young adults with ADHD compared with healthy controls. We examined whether these alterations were also found in their unaffected siblings, using a uniquely large sample. Methods We performed voxel-based morphometry analyses on MRI scans of patients with ADHD, their unaffected siblings and typically developing controls. We identified brain areas that differed between participants with ADHD and controls and investigated whether these areas were different in unaffected siblings. Influences of medication use, age, sex and IQ were considered. Results Our sample included 307 patients with ADHD, 169 unaffected siblings and 196 typically developing controls (mean age 17.2 [range 8–30] yr). Compared with controls, participants with ADHD had significantly smaller grey matter volume in 5 clusters located in the precentral gyrus, medial and orbitofrontal cortex, and (para)cingulate cortices. Unaffected siblings showed intermediate volumes significantly different from controls in 4 of these clusters (all except the precentral gyrus). Medication use, age, sex and IQ did not have an undue influence on the results. Limitations Our sample was heterogeneous, most participants with ADHD were taking medication, and the comparison was cross-sectional. Conclusion Brain areas involved in decision making, motivation, cognitive control and motor functioning were smaller in participants with ADHD than in controls. Investigation of unaffected siblings indicated familiality of 4 of the structural brain differences, supporting their potential in molecular genetic analyses in ADHD research. PMID:26679925

  10. What can volumes reveal about human brain evolution? A framework for bridging behavioral, histometric, and volumetric perspectives

    PubMed Central

    de Sousa, Alexandra A.; Proulx, Michael J.

    2014-01-01

    An overall relationship between brain size and cognitive ability exists across primates. Can more specific information about neural function be gleaned from cortical area volumes? Numerous studies have found significant relationships between brain structures and behaviors. However, few studies have speculated about brain structure-function relationships from the microanatomical to the macroanatomical level. Here we address this problem in comparative neuroanatomy, where the functional relevance of overall brain size and the sizes of cortical regions have been poorly understood, by considering comparative psychology, with measures of visual acuity and the perception of visual illusions. We outline a model where the macroscopic size (volume or surface area) of a cortical region (such as the primary visual cortex, V1) is related to the microstructure of discrete brain regions. The hypothesis developed here is that an absolutely larger V1 can process more information with greater fidelity due to having more neurons to represent a field of space. This is the first time that the necessary comparative neuroanatomical research at the microstructural level has been brought to bear on the issue. The evidence suggests that as the size of V1 increases: the number of neurons increases, the neuron density decreases, and the density of neuronal connections increases. Thus, we describe how information about gross neuromorphology, using V1 as a model for the study of other cortical areas, may permit interpretations of cortical function. PMID:25009469

  11. Altering blood flow does not reveal differences between nitrogen and helium kinetics in brain or in skeletal miracle in sheep.

    PubMed

    Doolette, David J; Upton, Richard N; Grant, Cliff

    2015-03-01

    In underwater diving, decompression schedules are based on compartmental models of nitrogen and helium tissue kinetics. However, these models are not based on direct measurements of nitrogen and helium kinetics. In isoflurane-anesthetized sheep, nitrogen and helium kinetics in the hind limb (n = 5) and brain (n = 5) were determined during helium-oxygen breathing and after return to nitrogen-oxygen breathing. Nitrogen and helium concentrations in arterial, femoral vein, and sagittal sinus blood samples were determined using headspace gas chromatography, and venous blood flows were monitored continuously using ultrasonic Doppler. The experiment was repeated at different states of hind limb blood flow and cerebral blood flow. Using arterial blood gas concentrations and blood flows as input, parameters and model selection criteria of various compartmental models of hind limb and brain were estimated by fitting to the observed venous gas concentrations. In both the hind limb and brain, nitrogen and helium kinetics were best fit by models with multiexponential kinetics. In the brain, there were no differences in nitrogen and helium kinetics. Hind limb models fit separately to the two gases indicated that nitrogen kinetics were slightly faster than helium, but models with the same kinetics for both gases fit the data well. In the hind limb and brain, the blood:tissue exchange of nitrogen is similar to that of helium. On the basis of these results, it is inappropriate to assign substantially different time constants for nitrogen and helium in all compartments in decompression algorithms.

  12. Single-Cell Transcriptomics Reveals a Population of Dormant Neural Stem Cells that Become Activated upon Brain Injury.

    PubMed

    Llorens-Bobadilla, Enric; Zhao, Sheng; Baser, Avni; Saiz-Castro, Gonzalo; Zwadlo, Klara; Martin-Villalba, Ana

    2015-09-01

    Heterogeneous pools of adult neural stem cells (NSCs) contribute to brain maintenance and regeneration after injury. The balance of NSC activation and quiescence, as well as the induction of lineage-specific transcription factors, may contribute to diversity of neuronal and glial fates. To identify molecular hallmarks governing these characteristics, we performed single-cell sequencing of an unbiased pool of adult subventricular zone NSCs. This analysis identified a discrete, dormant NSC subpopulation that already expresses distinct combinations of lineage-specific transcription factors during homeostasis. Dormant NSCs enter a primed-quiescent state before activation, which is accompanied by downregulation of glycolytic metabolism, Notch, and BMP signaling and a concomitant upregulation of lineage-specific transcription factors and protein synthesis. In response to brain ischemia, interferon gamma signaling induces dormant NSC subpopulations to enter the primed-quiescent state. This study unveils general principles underlying NSC activation and lineage priming and opens potential avenues for regenerative medicine in the brain. PMID:26235341

  13. Small-World Brain Functional Networks in Children With Attention-Deficit/Hyperactivity Disorder Revealed by EEG Synchrony.

    PubMed

    Liu, Tian; Chen, Yanni; Lin, Pan; Wang, Jue

    2015-07-01

    We investigated the topologic properties of human brain attention-related functional networks associated with Multi-Source Interference Task (MSIT) performance using electroencephalography (EEG). Data were obtained from 13 children diagnosed with attention-deficit/hyperactivity disorder (ADHD) and 13 normal control children. Functional connectivity between all pairwise combinations of EEG channels was established by calculating synchronization likelihood (SL). The cluster coefficients and path lengths were computed as a function of degree K. The results showed that brain attention functional networks of normal control subjects had efficient small-world topologic properties, whereas these topologic properties were altered in ADHD. In particular, increased local characteristics combined with decreased global characteristics in ADHD led to a disorder-related shift of the network topologic structure toward ordered networks. These findings are consistent with a hypothesis of dysfunctional segregation and integration of the brain in ADHD, and enhance our understanding of the underlying pathophysiologic mechanism of this illness.

  14. White matter tract oriented deformation predicts traumatic axonal brain injury and reveals rotational direction-specific vulnerabilities

    PubMed Central

    Sullivan, Sarah; Eucker, Stephanie A.; Gabrieli, David; Bradfield, Connor; Coats, Brittany; Maltese, Matthew R.; Lee, Jongho; Smith, Colin; Margulies, Susan S.

    2015-01-01

    A systematic correlation between finite element models (FEMs) and histopathology is needed to define deformation thresholds associated with traumatic brain injury (TBI). In this study, a FEM of a transected piglet brain was used to reverse engineer the range of optimal shear moduli for infant (5-day-old, 553-658 Pa) and 4-week old toddler piglet brain, (692-811 Pa) from comparisons with measured in situ tissue strains. The more mature brain modulus was found to have significant strain and strain rate dependencies not observed with the infant brain. Age-appropriate FEMs were then used to simulate experimental TBI in infant (n=36) and pre-adolescent (n=17) piglets undergoing a range of rotational head loads. The experimental animals were evaluated for the presence of clinically significant traumatic axonal injury (TAI), which was then correlated with FEM-calculated measures of overall and white matter tract-oriented tissue deformations, and used to identify the metric with the highest sensitivity and specificity for detecting TAI. The best predictors of TAI were the tract-oriented strain (6–7%), strain rate (38–40 s−1), and strain times strain rate (1.3–1.8 s−1) values exceeded by 90% of the brain. These tract-oriented strain and strain rate thresholds for TAI were comparable to those found in isolated axonal stretch studies. Furthermore, we proposed that the higher degree of agreement between tissue distortion aligned with white matter tracts and TAI may be the underlying mechanism responsible for more severe TAI after horizontal and sagittal head rotations in our porcine model of nonimpact TAI than coronal plane rotations. PMID:25547650

  15. Exome sequencing reveals a novel WDR45 frameshift mutation and inherited POLR3A heterozygous variants in a female with a complex phenotype and mixed brain MRI findings.

    PubMed

    Khalifa, Mohamed; Naffaa, Lena

    2015-08-01

    WDR45 and POLR3A are newly recognized genes; each is associated with a distinct neurodegenerative disease. WDR45 is an X-linked gene associated with a dominant form of Neurodegeneration with Brain Iron Accumulation (NBIA), manifested by progressive disabilities, dystonia, cognitive decline, spastic paraplegia, neuropsychiatric abnormalities and iron deposition in the basal ganglia on brain imaging. POLR3A, on the other hand, is an autosomal gene, and its mutations cause a recessive form of a hypomyelination with leukodystrophy disease, also known as 4H syndrome, characterized by congenital Hypomyelination with thinning of the corpus callosum, Hypodontia and Hypogonadotropic Hypogonadism. We report on a female child with severe intellectual disability, aphasia, short stature, ataxia, failure to thrive and structural brain abnormalities. Brain MRI obtained in late infancy showed hypomyelination involving the central periventricular white matter and thinning of the corpus callosum with no evidence of iron accumulation. Brain MRI obtained in childhood showed stable hypomyelination, with progressive iron accumulation in the basal ganglia, in particular in the globus pallidus and substantia nigra. Whole Exome Sequencing (WES) identified a novel WDR45 frameshift deleterious mutation in Exon 9 (c.587-588del) and also revealed three POLR3A missense heterozygous variants. The first is a maternally inherited novel missense variant in exon 4 (c.346A > G). Exon 13 carried two heterozygous missense variants, a maternally inherited variant (c.1724A > T) and a paternally inherited variant (1745G > A). These variants are considered likely damaging. The patient's complex clinical phenotype and mixed brain MRI findings might be attributed to the confounding effects of the expression of these two mutant genes.

  16. Brain-based decoding of mentally imagined film clips and sounds reveals experience-based information patterns in film professionals.

    PubMed

    de Borst, Aline W; Valente, Giancarlo; Jääskeläinen, Iiro P; Tikka, Pia

    2016-04-01

    In the perceptual domain, it has been shown that the human brain is strongly shaped through experience, leading to expertise in highly-skilled professionals. What has remained unclear is whether specialization also shapes brain networks underlying mental imagery. In our fMRI study, we aimed to uncover modality-specific mental imagery specialization of film experts. Using multi-voxel pattern analysis we decoded from brain activity of professional cinematographers and sound designers whether they were imagining sounds or images of particular film clips. In each expert group distinct multi-voxel patterns, specific for the modality of their expertise, were found during classification of imagery modality. These patterns were mainly localized in the occipito-temporal and parietal cortex for cinematographers and in the auditory cortex for sound designers. We also found generalized patterns across perception and imagery that were distinct for the two expert groups: they involved frontal cortex for the cinematographers and temporal cortex for the sound designers. Notably, the mental representations of film clips and sounds of cinematographers contained information that went beyond modality-specificity. We were able to successfully decode the implicit presence of film genre from brain activity during mental imagery in cinematographers. The results extend existing neuroimaging literature on expertise into the domain of mental imagery and show that experience in visual versus auditory imagery can alter the representation of information in modality-specific association cortices.

  17. Diffusion Tensor Imaging Reveals White Matter Injury in a Rat Model of Repetitive Blast-Induced Traumatic Brain Injury

    PubMed Central

    Calabrese, Evan; Du, Fu; Garman, Robert H.; Johnson, G. Allan; Riccio, Cory; Tong, Lawrence C.

    2014-01-01

    Abstract Blast-induced traumatic brain injury (bTBI) is one of the most common combat-related injuries seen in U.S. military personnel, yet relatively little is known about the underlying mechanisms of injury. In particular, the effects of the primary blast pressure wave are poorly understood. Animal models have proven invaluable for the study of primary bTBI, because it rarely occurs in isolation in human subjects. Even less is known about the effects of repeated primary blast wave exposure, but existing data suggest cumulative increases in brain damage with a second blast. MRI and, in particular, diffusion tensor imaging (DTI), have become important tools for assessing bTBI in both clinical and preclinical settings. Computational statistical methods such as voxelwise analysis have shown promise in localizing and quantifying bTBI throughout the brain. In this study, we use voxelwise analysis of DTI to quantify white matter injury in a rat model of repetitive primary blast exposure. Our results show a significant increase in microstructural damage with a second blast exposure, suggesting that primary bTBI may sensitize the brain to subsequent injury. PMID:24392843

  18. Functional magnetic resonance imaging reveals abnormal brain connectivity in EGR3 gene transfected rat model of schizophrenia.

    PubMed

    Song, Tianbin; Nie, Binbin; Ma, Ensen; Che, Jing; Sun, Shilong; Wang, Yuli; Shan, Baoci; Liu, Yawu; Luo, Senlin; Ma, Guolin; Li, Kefeng

    2015-05-01

    Schizophrenia is characterized by the disorder of "social brain". However, the alternation of connectivity density in brain areas of schizophrenia patients remains largely unknown. In this study, we successfully created a rat model of schizophrenia by the transfection of EGR3 gene into rat brain. We then investigated the connectivity density of schizophrenia susceptible regions in rat brain using functional magnetic resonance imaging (fMRI) in combination with multivariate Granger causality (GC) model. We found that the average signal strength in prefrontal lobe and hippocampus of schizophrenia model group was significantly higher than the control group. Bidirectional Granger causality connection was observed between hippocampus and thalamic in schizophrenia model group. Both connectivity density and Granger causality connection were changed in prefrontal lobe, hippocampus and thalamus after risperidone treatment. Our results indicated that fMRI in combination with GC connection analysis may be used as an important method in diagnosis of schizophrenia and evaluation the effect of antipsychotic treatment. These findings support the connectivity disorder hypothesis of schizophrenia and increase our understanding of the neural mechanisms of schizophrenia.

  19. Relationship between brain network pattern and cognitive performance of children revealed by MEG signals during free viewing of video.

    PubMed

    Duan, Fang; Watanabe, Katsumi; Yoshimura, Yuko; Kikuchi, Mitsuru; Minabe, Yoshio; Aihara, Kazuyuki

    2014-04-01

    Application of graph theory to analysis of functional networks in the brain is an important research trend. Extensive research on the resting state has shown a "small-world" organization of the brain network as a whole. However, the small-worldness of children's brain networks in a working state has not yet been well characterized. In this paper, we used a custom-made, child-sized magnetoencephalography (MEG) device to collect data from children while they were watching cartoon videos. Network structures were analyzed and compared with scores on the Kaufman Assessment Battery for Children (K-ABC). The results of network analysis showed that (1) the small-world scalar showed a negative correlation with the simultaneous processing raw score, a measure of visual processing (Gv) ability, and (2) the children with higher simultaneous processing raw scores possessed network structures that can be more efficient for local information processing than children with lower scores. These results were compatible with previous studies on the adult working state. Additional results obtained from further analysis of the frontal and occipital lobes indicated that high cognitive performance could represent better local efficiency in task-related sub-networks. Under free viewing of cartoon videos, brain networks were no longer confined to their strongest small-world states; connections became clustered in local areas such as the frontal and occipital lobes, which might be a more useful configuration for handling visual processing tasks.

  20. Exploratory metabolomic analyses reveal compounds correlated with lutein concentration in frontal cortex, hippocampus, and occipital cortex of human infant brain

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Lutein is a dietary carotenoid well known for its role as an antioxidant in the macula and recent reports implicate a role for lutein in cognitive function. Lutein is the dominant carotenoid in both pediatric and geriatric brain tissue. In addition, cognitive function in older adults correlated with...

  1. Brain networks engaged in audiovisual integration during speech perception revealed by persistent homology-based network filtration.

    PubMed

    Kim, Heejung; Hahm, Jarang; Lee, Hyekyoung; Kang, Eunjoo; Kang, Hyejin; Lee, Dong Soo

    2015-05-01

    The human brain naturally integrates audiovisual information to improve speech perception. However, in noisy environments, understanding speech is difficult and may require much effort. Although the brain network is supposed to be engaged in speech perception, it is unclear how speech-related brain regions are connected during natural bimodal audiovisual or unimodal speech perception with counterpart irrelevant noise. To investigate the topological changes of speech-related brain networks at all possible thresholds, we used a persistent homological framework through hierarchical clustering, such as single linkage distance, to analyze the connected component of the functional network during speech perception using functional magnetic resonance imaging. For speech perception, bimodal (audio-visual speech cue) or unimodal speech cues with counterpart irrelevant noise (auditory white-noise or visual gum-chewing) were delivered to 15 subjects. In terms of positive relationship, similar connected components were observed in bimodal and unimodal speech conditions during filtration. However, during speech perception by congruent audiovisual stimuli, the tighter couplings of left anterior temporal gyrus-anterior insula component and right premotor-visual components were observed than auditory or visual speech cue conditions, respectively. Interestingly, visual speech is perceived under white noise by tight negative coupling in the left inferior frontal region-right anterior cingulate, left anterior insula, and bilateral visual regions, including right middle temporal gyrus, right fusiform components. In conclusion, the speech brain network is tightly positively or negatively connected, and can reflect efficient or effortful processes during natural audiovisual integration or lip-reading, respectively, in speech perception.

  2. Effects of Perfluorooctanoic Acid on Metabolic Profiles in Brain and Liver of Mouse Revealed by a High-throughput Targeted Metabolomics Approach

    PubMed Central

    Yu, Nanyang; Wei, Si; Li, Meiying; Yang, Jingping; Li, Kan; Jin, Ling; Xie, Yuwei; Giesy, John P.; Zhang, Xiaowei; Yu, Hongxia

    2016-01-01

    Perfluorooctanoic acid (PFOA), a perfluoroalkyl acid, can result in hepatotoxicity and neurobehavioral effects in animals. The metabolome, which serves as a connection among transcriptome, proteome and toxic effects, provides pathway-based insights into effects of PFOA. Since understanding of changes in the metabolic profile during hepatotoxicity and neurotoxicity were still incomplete, a high-throughput targeted metabolomics approach (278 metabolites) was used to investigate effects of exposure to PFOA for 28 d on brain and liver of male Balb/c mice. Results of multivariate statistical analysis indicated that PFOA caused alterations in metabolic pathways in exposed individuals. Pathway analysis suggested that PFOA affected metabolism of amino acids, lipids, carbohydrates and energetics. Ten and 18 metabolites were identified as potential unique biomarkers of exposure to PFOA in brain and liver, respectively. In brain, PFOA affected concentrations of neurotransmitters, including serotonin, dopamine, norepinephrine, and glutamate in brain, which provides novel insights into mechanisms of PFOA-induced neurobehavioral effects. In liver, profiles of lipids revealed involvement of β-oxidation and biosynthesis of saturated and unsaturated fatty acids in PFOA-induced hepatotoxicity, while alterations in metabolism of arachidonic acid suggesting potential of PFOA to cause inflammation response in liver. These results provide insight into the mechanism and biomarkers for PFOA-induced effects. PMID:27032815

  3. Violence-related content in video game may lead to functional connectivity changes in brain networks as revealed by fMRI-ICA in young men.

    PubMed

    Zvyagintsev, M; Klasen, M; Weber, R; Sarkheil, P; Esposito, F; Mathiak, K A; Schwenzer, M; Mathiak, K

    2016-04-21

    In violent video games, players engage in virtual aggressive behaviors. Exposure to virtual aggressive behavior induces short-term changes in players' behavior. In a previous study, a violence-related version of the racing game "Carmageddon TDR2000" increased aggressive affects, cognitions, and behaviors compared to its non-violence-related version. This study investigates the differences in neural network activity during the playing of both versions of the video game. Functional magnetic resonance imaging (fMRI) recorded ongoing brain activity of 18 young men playing the violence-related and the non-violence-related version of the video game Carmageddon. Image time series were decomposed into functional connectivity (FC) patterns using independent component analysis (ICA) and template-matching yielded a mapping to established functional brain networks. The FC patterns revealed a decrease in connectivity within 6 brain networks during the violence-related compared to the non-violence-related condition: three sensory-motor networks, the reward network, the default mode network (DMN), and the right-lateralized frontoparietal network. Playing violent racing games may change functional brain connectivity, in particular and even after controlling for event frequency, in the reward network and the DMN. These changes may underlie the short-term increase of aggressive affects, cognitions, and behaviors as observed after playing violent video games. PMID:26855192

  4. Violence-related content in video game may lead to functional connectivity changes in brain networks as revealed by fMRI-ICA in young men.

    PubMed

    Zvyagintsev, M; Klasen, M; Weber, R; Sarkheil, P; Esposito, F; Mathiak, K A; Schwenzer, M; Mathiak, K

    2016-04-21

    In violent video games, players engage in virtual aggressive behaviors. Exposure to virtual aggressive behavior induces short-term changes in players' behavior. In a previous study, a violence-related version of the racing game "Carmageddon TDR2000" increased aggressive affects, cognitions, and behaviors compared to its non-violence-related version. This study investigates the differences in neural network activity during the playing of both versions of the video game. Functional magnetic resonance imaging (fMRI) recorded ongoing brain activity of 18 young men playing the violence-related and the non-violence-related version of the video game Carmageddon. Image time series were decomposed into functional connectivity (FC) patterns using independent component analysis (ICA) and template-matching yielded a mapping to established functional brain networks. The FC patterns revealed a decrease in connectivity within 6 brain networks during the violence-related compared to the non-violence-related condition: three sensory-motor networks, the reward network, the default mode network (DMN), and the right-lateralized frontoparietal network. Playing violent racing games may change functional brain connectivity, in particular and even after controlling for event frequency, in the reward network and the DMN. These changes may underlie the short-term increase of aggressive affects, cognitions, and behaviors as observed after playing violent video games.

  5. Effects of Perfluorooctanoic Acid on Metabolic Profiles in Brain and Liver of Mouse Revealed by a High-throughput Targeted Metabolomics Approach

    NASA Astrophysics Data System (ADS)

    Yu, Nanyang; Wei, Si; Li, Meiying; Yang, Jingping; Li, Kan; Jin, Ling; Xie, Yuwei; Giesy, John P.; Zhang, Xiaowei; Yu, Hongxia

    2016-04-01

    Perfluorooctanoic acid (PFOA), a perfluoroalkyl acid, can result in hepatotoxicity and neurobehavioral effects in animals. The metabolome, which serves as a connection among transcriptome, proteome and toxic effects, provides pathway-based insights into effects of PFOA. Since understanding of changes in the metabolic profile during hepatotoxicity and neurotoxicity were still incomplete, a high-throughput targeted metabolomics approach (278 metabolites) was used to investigate effects of exposure to PFOA for 28 d on brain and liver of male Balb/c mice. Results of multivariate statistical analysis indicated that PFOA caused alterations in metabolic pathways in exposed individuals. Pathway analysis suggested that PFOA affected metabolism of amino acids, lipids, carbohydrates and energetics. Ten and 18 metabolites were identified as potential unique biomarkers of exposure to PFOA in brain and liver, respectively. In brain, PFOA affected concentrations of neurotransmitters, including serotonin, dopamine, norepinephrine, and glutamate in brain, which provides novel insights into mechanisms of PFOA-induced neurobehavioral effects. In liver, profiles of lipids revealed involvement of β-oxidation and biosynthesis of saturated and unsaturated fatty acids in PFOA-induced hepatotoxicity, while alterations in metabolism of arachidonic acid suggesting potential of PFOA to cause inflammation response in liver. These results provide insight into the mechanism and biomarkers for PFOA-induced effects.

  6. Regional TNFα mapping in the brain reveals the striatum as a neuroinflammatory target after ventricular fibrillation cardiac arrest in rats☆

    PubMed Central

    Janata, Andreas; Magnet, Ingrid A.M.; Uray, Thomas; Stezoski, Jason P.; Janesko-Feldman, Keri; Tisherman, Samuel A.; Kochanek, Patrick M.; Drabek, Tomas

    2014-01-01

    Cardiac arrest (CA) triggers neuroinflammation that could play a role in a delayed neuronal death. In our previously established rat model of ventricular fibrillation (VF) CA characterized by extensive neuronal death, we tested the hypothesis that individual brain regions have specific neuroinflammatory responses, as reflected by regional brain tissue levels of tumor necrosis factor (TNF)α and other cytokines. In a prospective study, rats were randomized to 6 min (CA6), 8 min (CA8) or 10 min (CA10) of VF CA, or sham group. Cortex, striatum, hippocampus and cerebellum were evaluated for TNFα and interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12 and interferon gamma at 3 h, 6 h or 14 d after CA by ELISA and Luminex. Immunohistochemistry was used to determine the cell source of TNFα. CA resulted in a selective TNFα response with significant regional and temporal differences. At 3 h after CA, TNFα-levels increased in all regions depending on the duration of the insult. The most pronounced increase was observed in striatum that showed 20-fold increase in CA10 vs. sham, and 3-fold increase vs. CA6 or CA8 group, respectively (p < 0.01). TNFα levels in striatum decreased between 3 h and 6 h, but increased in other regions between 3 h and 14 d. TNFα levels remained twofold higher in CA6 vs. shams across brain regions at 14 d (p < 0.01). In contrast to pronounced TNFα response, other cytokines showed only a minimal increase in CA6 and CA8 groups vs. sham in all brain regions with the exception that IL-1β increased twofold in cerebellum and striatum (p < 0.01). TNFα colocalized with neurons. In conclusion, CA produced a duration-dependent acute TNFα response, with dramatic increase in the striatum where TNFα colocalized with neurons. Increased TNFα levels persist for at least two weeks. This TNFα surge contrasts the lack of an acute increase in other cytokines in brain after CA. Given that striatum is a selectively vulnerable brain region, our data

  7. Unexpected elastic softening in δ -plutonium

    NASA Astrophysics Data System (ADS)

    Migliori, A.; Ledbetter, H.; Lawson, A. C.; Ramirez, A. P.; Miller, D. A.; Betts, J. B.; Ramos, M.; Lashley, J. C.

    2006-02-01

    Elastic-constant measurements on a Pu-2.4at.% Ga quasiisotropic polycrystal reveal remarkable elastic softening as temperature increases from ambient to 500K . Unexpected softening appears in both the bulk modulus B and the shear modulus G , thus in all quasiisotropic elastic stiffnesses such as the Young modulus and the Lamé constants. The dB/dT slope gives a (lattice) Grüneisen parameter γ=3.7 , much higher than a typical fcc-metallic-element value of 2.4±0.5 . Especially, this high γ from dB/dT measurements disagrees strongly with the γ=-0.26±0.5 from volume measurements. The dB/dT slope exceeds that measured previously at lower temperatures. Also, it exceeds that expected from high-temperature Debye-Waller-factor measurements. A two-level model used successfully previously to interpret this alloy’s unusually low thermal expansion also describes the large dB/dT . We comment on possible explanations for plutonium’s odd anharmonic behavior. These concepts include magnetism, 5f -electron localization-delocalization, and vibrational entropy. Our measurements on the Pu-Ga polycrystal agree remarkably well with a Kröner-theory average of previous measurements on a same-composition monocrystal.

  8. Rapid Response: Unexpected Jupiter Impact

    NASA Astrophysics Data System (ADS)

    Simon-Miller, Amy

    2009-07-01

    On 3 June 2010, amateur astronomers A. Wesley and C. Go independently captured observations of an impact on Jupiter: the bright flash of an impact itself, not the dark aftermath as seen in 2009. This event was completely unexpected given the recent impact in 2009, and contradicts recently revised predictions of jovian impact rates. Three circumstances make this 2009 event unique: first, the event was captured on video; second, it was on the jovian day-side and hence fully visible from Earth; and third, it was at low latitude {i.e., favorably placed on the planet}. These factors will permit a lightcurve to be extracted, which is critical for determining the energy of the explosion and hence the size of the impacting body {not available for the 2009 event and available for only a few 1994 events by Galileo}. As of this writing, no dark impact site has been detected with telescopes of any aperture, including the Gemini North telescope. Hubble may be the only facility with high enough spatial resolution to detect the 2010 impact site. If Hubble images show a site, then the body's trajectory might be obtainable. If no site is detected, then Hubble will confirm that this is the first observation of a meteor on another atmosphere-bearing planet. If an event of this size occurred on Earth, it would be likely be termed a Type 1 Low-Altitude Airburst, like Tunguska or larger. Thus, this new event could become the best-observed analogue of a terrestrial airburst of the size that dominates the impact threat to humans. The observations we propose should provide independent constraints on penetration depth and atmospheric effects. This data will strongly inform our understanding of terrestrial airbursts and allow better quantification of the associated threat. We request a single orbit to image the impact latitude on the planet's central meridian. Of critical importance are Hubble's unique UV sensitivity {critical for assessing aspects of the 2009 impact, and not obtainable from

  9. Environmental changes in oxygen tension reveal ROS-dependent neurogenesis and regeneration in the adult newt brain.

    PubMed

    Hameed, L Shahul; Berg, Daniel A; Belnoue, Laure; Jensen, Lasse D; Cao, Yihai; Simon, András

    2015-01-01

    Organisms need to adapt to the ecological constraints in their habitat. How specific processes reflect such adaptations are difficult to model experimentally. We tested whether environmental shifts in oxygen tension lead to events in the adult newt brain that share features with processes occurring during neuronal regeneration under normoxia. By experimental simulation of varying oxygen concentrations, we show that hypoxia followed by re-oxygenation lead to neuronal death and hallmarks of an injury response, including activation of neural stem cells ultimately leading to neurogenesis. Neural stem cells accumulate reactive oxygen species (ROS) during re-oxygenation and inhibition of ROS biosynthesis counteracts their proliferation as well as neurogenesis. Importantly, regeneration of dopamine neurons under normoxia also depends on ROS-production. These data demonstrate a role for ROS-production in neurogenesis in newts and suggest that this role may have been recruited to the capacity to replace lost neurons in the brain of an adult vertebrate. PMID:26485032

  10. Environmental changes in oxygen tension reveal ROS-dependent neurogenesis and regeneration in the adult newt brain.

    PubMed

    Hameed, L Shahul; Berg, Daniel A; Belnoue, Laure; Jensen, Lasse D; Cao, Yihai; Simon, András

    2015-10-20

    Organisms need to adapt to the ecological constraints in their habitat. How specific processes reflect such adaptations are difficult to model experimentally. We tested whether environmental shifts in oxygen tension lead to events in the adult newt brain that share features with processes occurring during neuronal regeneration under normoxia. By experimental simulation of varying oxygen concentrations, we show that hypoxia followed by re-oxygenation lead to neuronal death and hallmarks of an injury response, including activation of neural stem cells ultimately leading to neurogenesis. Neural stem cells accumulate reactive oxygen species (ROS) during re-oxygenation and inhibition of ROS biosynthesis counteracts their proliferation as well as neurogenesis. Importantly, regeneration of dopamine neurons under normoxia also depends on ROS-production. These data demonstrate a role for ROS-production in neurogenesis in newts and suggest that this role may have been recruited to the capacity to replace lost neurons in the brain of an adult vertebrate.

  11. A Voxel-Based Morphometry Study Reveals Local Brain Structural Alterations Associated with Ambient Fine Particles in Older Women

    PubMed Central

    Casanova, Ramon; Wang, Xinhui; Reyes, Jeanette; Akita, Yasuyuki; Serre, Marc L.; Vizuete, William; Chui, Helena C.; Driscoll, Ira; Resnick, Susan M.; Espeland, Mark A.; Chen, Jiu-Chiuan; Wassertheil-Smoller, Sylvia; Goodwin, Mimi; DeNise, Richard; Lipton, Michael; Hannigan, James; Carpini, Anthony; Noble, David; Guzman, Wilton; Kotchen, Jane Morley; Goveas, Joseph; Kerwin, Diana; Ulmer, John; Censky, Steve; Flinton, Troy; Matusewic, Tracy; Prost, Robert; Stefanick, Marcia L.; Swope, Sue; Sawyer-Glover, Anne Marie; Hartley, Susan; Jackson, Rebecca; Hallarn, Rose; Kennedy, Bonnie; Bolognone, Jill; Casimir, Lindsay; Kochis, Amanda; Robbins, John; Zaragoza, Sophia; Carter, Cameron; Ryan, John; Macias, Denise; Sonico, Jerry; Nathan, Lauren; Voigt, Barbara; Villablanca, Pablo; Nyborg, Glen; Godinez, Sergio; Perrymann, Adele; Limacher, Marian; Anderson, Sheila; Toombs, Mary Ellen; Bennett, Jeffrey; Jones, Kevin; Brum, Sandy; Chatfield, Shane; Vantrees, Kevin; Robinson, Jennifer; Wilson, Candy; Koch, Kevin; Hart, Suzette; Carroll, Jennifer; Cherrico, Mary; Ockene, Judith; Churchill, Linda; Fellows, Douglas; Serio, Anthony; Jackson, Sharon; Spavich, Deidre; Margolis, Karen; Bjerk, Cindy; Truwitt, Chip; Peitso, Margaret; Camcrena, Alexa; Grim, Richard; Levin, Julie; Perron, Mary; Brunner, Robert; Golding, Ross; Pansky, Leslie; Arguello, Sandie; Hammons, Jane; Peterson, Nikki; Murphy, Carol; Morgan, Maggie; Castillo, Mauricio; Beckman, Thomas; Huang, Benjamin; Kuller, Lewis; McHugh, Pat; Meltzer, Carolyn; Davis, Denise; Davis, Joyce; Kost, Piera; Lucas, Kim; Potter, Tom; Tarr, Lee; Shumaker, Sally; Espeland, Mark; Coker, Laura; Williamson, Jeff; Felton, Debbie; Gleiser, LeeAnn; Rapp, Steve; Legault, Claudine; Dailey, Maggie; Casanova, Ramon; Robertson, Julia; Hogan, Patricia; Gaussoin, Sarah; Nance, Pam; Summerville, Cheryl; Peral, Ricardo; Tan, Josh; Bryan, Nick; Davatzikos, Christos; Desiderio, Lisa; Buckholtz, Neil; Molchan, Susan; Resnick, Susan; Rossouw, Jacques; Pottern, Linda

    2016-01-01

    Objective: Exposure to ambient fine particulate matter (PM2.5: PM with aerodynamic diameters < 2.5 μm) has been linked with cognitive deficits in older adults. Using fine-grained voxel-wise analyses, we examined whether PM2.5 exposure also affects brain structure. Methods: Brain MRI data were obtained from 1365 women (aged 71–89) in the Women's Health Initiative Memory Study and local brain volumes were estimated using RAVENS (regional analysis of volumes in normalized space). Based on geocoded residential locations and air monitoring data from the U.S. Environmental Protection Agency, we employed a spatiotemporal model to estimate long-term (3-year average) exposure to ambient PM2.5 preceding MRI scans. Voxel-wise linear regression models were fit separately to gray matter (GM) and white matter (WM) maps to analyze associations between brain structure and PM2.5 exposure, with adjustment for potential confounders. Results: Increased PM2.5 exposure was associated with smaller volumes in both cortical GM and subcortical WM areas. For GM, associations were clustered in the bilateral superior, middle, and medial frontal gyri. For WM, the largest clusters were in the frontal lobe, with smaller clusters in the temporal, parietal, and occipital lobes. No statistically significant associations were observed between PM2.5 exposure and hippocampal volumes. Conclusions: Long-term PM2.5 exposures may accelerate loss of both GM and WM in older women. While our previous work linked smaller WM volumes to PM2.5, this is the first neuroimaging study reporting associations between air pollution exposure and smaller volumes of cortical GM. Our data support the hypothesized synaptic neurotoxicity of airborne particles. PMID:27790103

  12. Effects of Hormone Therapy on Brain Volumes Changes of Postmenopausal Women Revealed by Optimally-Discriminative Voxel-Based Morphometry

    PubMed Central

    Zhang, Tianhao; Casanova, Ramon; Resnick, Susan M.; Manson, JoAnn E.; Baker, Laura D.; Padual, Claudia B.; Kuller, Lewis H.; Bryan, R. Nick; Espeland, Mark A.; Davatzikos, Christos

    2016-01-01

    Backgrounds The Women's Health Initiative Memory Study Magnetic Resonance Imaging (WHIMS-MRI) provides an opportunity to evaluate how menopausal hormone therapy (HT) affects the structure of older women’s brains. Our earlier work based on region of interest (ROI) analysis demonstrated potential structural changes underlying adverse effects of HT on cognition. However, the ROI-based analysis is limited in statistical power and precision, and cannot provide fine-grained mapping of whole-brain changes. Methods We aimed to identify local structural differences between HT and placebo groups from WHIMS-MRI in a whole-brain refined level, by using a novel method, named Optimally-Discriminative Voxel-Based Analysis (ODVBA). ODVBA is a recently proposed imaging pattern analysis approach for group comparisons utilizing a spatially adaptive analysis scheme to accurately locate areas of group differences, thereby providing superior sensitivity and specificity to detect the structural brain changes over conventional methods. Results Women assigned to HT treatments had significant Gray Matter (GM) losses compared to the placebo groups in the anterior cingulate and the adjacent medial frontal gyrus, and the orbitofrontal cortex, which persisted after multiple comparison corrections. There were no regions where HT was significantly associated with larger volumes compared to placebo, although a trend of marginal significance was found in the posterior cingulate cortical area. The CEE-Alone and CEE+MPA groups, although compared with different placebo controls, demonstrated similar effects according to the spatial patterns of structural changes. Conclusions HT had adverse effects on GM volumes and risk for cognitive impairment and dementia in older women. These findings advanced our understanding of the neurobiological underpinnings of HT effects. PMID:26974440

  13. Regional Variation of White Matter Development in the Cat Brain Revealed by Ex Vivo Diffusion MR Tractography

    PubMed Central

    Dai, Guangping; Das, Avilash; Hayashi, Emiko; Chen, Qin; Takahashi, Emi

    2016-01-01

    Three-dimensional reconstruction of developing fiber pathways is essential to assessing the developmental course of fiber pathways in the whole brain. We applied diffusion spectrum imaging (DSI) tractography to five juvenile ex vivo cat brains at postnatal day (P) 35, when the degree of myelination varies across brain regions. We quantified diffusion properties (fractional anisotropy [FA] and apparent diffusion coefficient [ADC]) and other measurements (number, volume, and voxel count) on reconstructed pathways for projection (cortico-spinal and thalamo-cortical), corpus callosal, limbic (cingulum and fornix), and association (cortico-cortical) pathways, and characterized regional differences in maturation patterns by assessing diffusion properties. FA values were significantly higher in cortico-cortical pathways within the right hemisphere compared to those within the left hemisphere, while the other measurements for the cortico-cortical pathways within the hemisphere did not show asymmetry. ADC values were not asymmetric in both types of pathways. Interestingly, tract count and volume were significantly larger in the left thalamo-cortical pathways compared to the right thalamo-cortical pathways. The bilateral thalamo-cortical pathways showed high FA values compared to the other fiber pathways. On the other hand, ADC values did not show any differences across pathways studied. These results demonstrate that DSI tractography successfully depicted regional variations of white matter tracts during development when myelination is incomplete. Low FA and high ADC values in the cingulum bundle suggest that the cingulum bundle is less mature than the others at this developmental stage. PMID:27568056

  14. Simultaneous Brain-Cervical Cord fMRI Reveals Intrinsic Spinal Cord Plasticity during Motor Sequence Learning.

    PubMed

    Vahdat, Shahabeddin; Lungu, Ovidiu; Cohen-Adad, Julien; Marchand-Pauvert, Veronique; Benali, Habib; Doyon, Julien

    2015-06-01

    The spinal cord participates in the execution of skilled movements by translating high-level cerebral motor representations into musculotopic commands. Yet, the extent to which motor skill acquisition relies on intrinsic spinal cord processes remains unknown. To date, attempts to address this question were limited by difficulties in separating spinal local effects from supraspinal influences through traditional electrophysiological and neuroimaging methods. Here, for the first time, we provide evidence for local learning-induced plasticity in intact human spinal cord through simultaneous functional magnetic resonance imaging of the brain and spinal cord during motor sequence learning. Specifically, we show learning-related modulation of activity in the C6-C8 spinal region, which is independent from that of related supraspinal sensorimotor structures. Moreover, a brain-spinal cord functional connectivity analysis demonstrates that the initial linear relationship between the spinal cord and sensorimotor cortex gradually fades away over the course of motor sequence learning, while the connectivity between spinal activity and cerebellum gains strength. These data suggest that the spinal cord not only constitutes an active functional component of the human motor learning network but also contributes distinctively from the brain to the learning process. The present findings open new avenues for rehabilitation of patients with spinal cord injuries, as they demonstrate that this part of the central nervous system is much more plastic than assumed before. Yet, the neurophysiological mechanisms underlying this intrinsic functional plasticity in the spinal cord warrant further investigations.

  15. Functional genomics reveals dysregulation of cortical olfactory receptors in Parkinson disease: novel putative chemoreceptors in the human brain.

    PubMed

    Garcia-Esparcia, Paula; Schlüter, Agatha; Carmona, Margarita; Moreno, Jesús; Ansoleaga, Belen; Torrejón-Escribano, Benjamín; Gustincich, Stefano; Pujol, Aurora; Ferrer, Isidre

    2013-06-01

    Parkinson disease (PD) is no longer considered a complex motor disorder but rather a systemic disease with variable nonmotor deficits that may include impaired olfaction, depression, mood and sleep disorders, and altered cortical function. Increasing evidence indicates that multiple metabolic defects occur in regions outside the substantia nigra, including the cerebral cortex, even at premotor stages of the disease. We investigated changes in gene expression in the frontal cortex in PD patient brains using a transcriptomics approach. Functional genomics analysis indicated that cortical olfactory receptors (ORs) and taste receptors (TASRs) are altered in PD patients. Olfactory receptors OR2L13, OR1E1, OR2J3, OR52L1, and OR11H1 and taste receptors TAS2R5 and TAS2R50 were downregulated, but TAS2R10 and TAS2R13 were upregulated at premotor and parkinsonian stages in the frontal cortex area 8 in PD patient brains. Furthermore, we present novel evidence that, in addition to the ORs, obligate downstream components of OR function adenylyl cyclase 3 and olfactory G protein (Gαolf), OR transporters, receptor transporter proteins 1 and 2 and receptor expression enhancing protein 1, and OR xenobiotic removing UDP-glucuronosyltransferase 1 family polypeptide A6 are widely expressed in neurons of the cerebral cortex and other regions of the adult human brain. Together, these findings support the concept that ORs and TASRs in the cerebral cortex may have novel physiologic functions that are affected in PD patients.

  16. Monoclonal antibodies to a 100-kd protein reveal abundant A beta-negative plaques throughout gray matter of Alzheimer's disease brains.

    PubMed Central

    Schmidt, M. L.; Lee, V. M.; Forman, M.; Chiu, T. S.; Trojanowski, J. Q.

    1997-01-01

    Here we describe the initial characterization of a 100-kd protein recognized by four new monoclonal antibodies that reveal abundant and unique plaque-like lesions throughout gray matter of Alzheimer's disease brains. This 100-kd protein and these new plaque-like lesions were identified by four monoclonal antibodies raised to immunogens extracted from Alzheimer's disease neurofibrillary abnormalities. However, these antibodies did not recognize hyperphosphorylated tau in Western blots or neurofibrillary lesions by immunohistochemistry. As all of these antibodies displayed similar properties, one, AMY117, was used to characterize the new plaque-like lesions in detail. These studies demonstrated that AMY117-positive plaques were not visualized by amyloid stains and never co-localized with A beta deposits, although AMY117-positive and A beta-positive lesions frequently occurred in the same cortical and subcortical gray matter regions. Abundant AMY117-positive plaques were found in the brains of all 32 sporadic Alzheimer's disease patients and all 6 elderly Down's syndrome subjects. Although AMY117-positive plaques also were seen in the brains of nondemented patients with numerous A beta deposits. AMY117-positive plaques were rare or absent in the brains of other elderly controls and patients with other neurodegenerative or neuropsychiatric disorders. We conclude that the AMY117-positive plaques described here for the first time are major lesions of the Alzheimer's disease brain. Thus, it will be important to elucidate the role played by the 100-kd protein and the AMY117 plaques in the etiology and pathogenesis of Alzheimer's disease. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:9212733

  17. FTIR Imaging of Brain Tissue Reveals Crystalline Creatine Deposits Are an ex Vivo Marker of Localized Ischemia during Murine Cerebral Malaria: General Implications for Disease Neurochemistry

    PubMed Central

    2012-01-01

    Phosphocreatine is a major cellular source of high energy phosphates, which is crucial to maintain cell viability under conditions of impaired metabolic states, such as decreased oxygen and energy availability (i.e., ischemia). Many methods exist for the bulk analysis of phosphocreatine and its dephosphorylated product creatine; however, no method exists to image the distribution of creatine or phosphocreatine at the cellular level. In this study, Fourier transform infrared (FTIR) spectroscopic imaging has revealed the ex vivo development of creatine microdeposits in situ in the brain region most affected by the disease, the cerebellum of cerebral malaria (CM) diseased mice; however, such deposits were also observed at significantly lower levels in the brains of control mice and mice with severe malaria. In addition, the number of deposits was observed to increase in a time-dependent manner during dehydration post tissue cutting. This challenges the hypotheses in recent reports of FTIR spectroscopic imaging where creatine microdeposits found in situ within thin sections from epileptic, Alzheimer’s (AD), and amlyoid lateral sclerosis (ALS) diseased brains were proposed to be disease specific markers and/or postulated to contribute to the brain pathogenesis. As such, a detailed investigation was undertaken, which has established that the creatine microdeposits exist as the highly soluble HCl salt or zwitterion and are an ex-vivo tissue processing artifact and, hence, have no effect on disease pathogenesis. They occur as a result of creatine crystallization during dehydration (i.e., air-drying) of thin sections of brain tissue. As ischemia and decreased aerobic (oxidative metabolism) are common to many brain disorders, regions of elevated creatine-to-phosphocreatine ratio are likely to promote crystal formation during tissue dehydration (due to the lower water solubility of creatine relative to phosphocreatine). The results of this study have demonstrated that

  18. Saami and Berbers--an unexpected mitochondrial DNA link.

    PubMed

    Achilli, Alessandro; Rengo, Chiara; Battaglia, Vincenza; Pala, Maria; Olivieri, Anna; Fornarino, Simona; Magri, Chiara; Scozzari, Rosaria; Babudri, Nora; Santachiara-Benerecetti, A Silvana; Bandelt, Hans-Jürgen; Semino, Ornella; Torroni, Antonio

    2005-05-01

    The sequencing of entire human mitochondrial DNAs belonging to haplogroup U reveals that this clade arose shortly after the "out of Africa" exit and rapidly radiated into numerous regionally distinct subclades. Intriguingly, the Saami of Scandinavia and the Berbers of North Africa were found to share an extremely young branch, aged merely approximately 9,000 years. This unexpected finding not only confirms that the Franco-Cantabrian refuge area of southwestern Europe was the source of late-glacial expansions of hunter-gatherers that repopulated northern Europe after the Last Glacial Maximum but also reveals a direct maternal link between those European hunter-gatherer populations and the Berbers.

  19. Amish Lifestyle Brings Unexpected Benefit: Less Asthma

    MedlinePlus

    ... 160228.html Amish Lifestyle Brings Unexpected Benefit: Less Asthma Finding suggests exposing kids to lots of allergens, ... rest of the population -- much lower rates of asthma. "We found Amish children had extremely low levels ...

  20. Manganese-enhanced magnetic resonance imaging reveals increased DOI-induced brain activity in a mouse model of schizophrenia

    PubMed Central

    Malkova, Natalia V.; Gallagher, Joseph J.; Yu, Collin Z.; Jacobs, Russell E.; Patterson, Paul H.

    2014-01-01

    Maternal infection during pregnancy increases the risk for schizophrenia in offspring. In rodent models, maternal immune activation (MIA) yields offspring with schizophrenia-like behaviors. None of these behaviors are, however, specific to schizophrenia. The presence of hallucinations is a key diagnostic symptom of schizophrenia. In mice, this symptom can be defined as brain activation in the absence of external stimuli, which can be mimicked by administration of hallucinogens. We find that, compared with controls, adult MIA offspring display an increased stereotypical behavioral response to the hallucinogen 2,5-dimethoxy-4-iodoamphetamine (DOI), an agonist for serotonin receptor 2A (5-HT2AR). This may be explained by increased levels of 5-HT2AR and downstream signaling molecules in unstimulated MIA prefrontal cortex (PFC). Using manganese-enhanced magnetic resonance imaging to identify neuronal activation elicited by DOI administration, we find that, compared with controls, MIA offspring exhibit a greater manganese (Mn2+) accumulation in several brain areas, including the PFC, thalamus, and striatum. The parafascicular thalamic nucleus, which plays the role in the pathogenesis of hallucinations, is activated by DOI in MIA offspring only. Additionally, compared with controls, MIA offspring demonstrate higher DOI-induced expression of early growth response protein 1, cyclooxygenase-2, and brain-derived neurotrophic factor in the PFC. Chronic treatment with the 5-HT2AR antagonist ketanserin reduces DOI-induced head twitching in MIA offspring. Thus, the MIA mouse model can be successfully used to investigate activity induced by DOI in awake, behaving mice. Moreover, manganese-enhanced magnetic resonance imaging is a useful, noninvasive method for accurately measuring this type of activity. PMID:24889602

  1. Immediate early gene expression reveals interactions between social and nicotine rewards on brain activity in adolescent male rats.

    PubMed

    Bastle, Ryan M; Peartree, Natalie A; Goenaga, Julianna; Hatch, Kayla N; Henricks, Angela; Scott, Samantha; Hood, Lauren E; Neisewander, Janet L

    2016-10-15

    Smoking initiation predominantly occurs during adolescence, often in the presence of peers. Therefore, understanding the neural mechanisms underlying the rewarding effects of nicotine and social stimuli is vital. Using the conditioned place preference (CPP) procedure, we measured immediate early gene (IEG) expression in animals following exposure either to a reward-conditioned environment or to the unconditioned stimuli (US). Adolescent, male rats were assigned to the following CPP US conditions: (1) Saline+Isolated, (2) Nicotine+Isolated, (3) Saline+Social, or (4) Nicotine+Social. For Experiment 1, brain tissue was collected 90min following the CPP expression test and processed for Fos immunohistochemistry. We found that rats conditioned with nicotine with or without a social partner exhibited CPP; however, we found no group differences in Fos expression in any brain region analyzed, with the exception of the nucleus accumbens core that exhibited a social-induced attenuation in Fos expression. For Experiment 2, brain tissue was collected 90min following US exposure during the last conditioning session. We found social reward-induced increases in IEG expression in striatal and amydalar subregions. In contrast, nicotine reduced IEG expression in prefrontal and striatal subregions. Reward interactions were also found in the dorsolateral striatum, basolateral amygdala, and ventral tegmental area where nicotine alone attenuated IEG expression and social reward reversed this effect. These results suggest that in general social rewards enhance, whereas nicotine attenuates, activation of mesocorticolimbic regions; however, the rewards given together interact to enhance activation in some regions. The findings contribute to knowledge of how a social environment influences nicotine effects.

  2. Integration of miRNA and Protein Profiling Reveals Coordinated Neuroadaptations in the Alcohol-Dependent Mouse Brain

    PubMed Central

    Gorini, Giorgio; Nunez, Yury O.; Mayfield, R. Dayne

    2013-01-01

    The molecular mechanisms underlying alcohol dependence involve different neurochemical systems and are brain region-dependent. Chronic Intermittent Ethanol (CIE) procedure, combined with a Two-Bottle Choice voluntary drinking paradigm, represents one of the best available animal models for alcohol dependence and relapse drinking. MicroRNAs, master regulators of the cellular transcriptome and proteome, can regulate their targets in a cooperative, combinatorial fashion, ensuring fine tuning and control over a large number of cellular functions. We analyzed cortex and midbrain microRNA expression levels using an integrative approach to combine and relate data to previous protein profiling from the same CIE-subjected samples, and examined the significance of the data in terms of relative contribution to alcohol consumption and dependence. MicroRNA levels were significantly altered in CIE-exposed dependent mice compared with their non-dependent controls. More importantly, our integrative analysis identified modules of coexpressed microRNAs that were highly correlated with CIE effects and predicted target genes encoding differentially expressed proteins. Coexpressed CIE-relevant proteins, in turn, were often negatively correlated with specific microRNA modules. Our results provide evidence that microRNA-orchestrated translational imbalances are driving the behavioral transition from alcohol consumption to dependence. This study represents the first attempt to combine ex vivo microRNA and protein expression on a global scale from the same mammalian brain samples. The integrative systems approach used here will improve our understanding of brain adaptive changes in response to drug abuse and suggests the potential therapeutic use of microRNAs as tools to prevent or compensate multiple neuroadaptations underlying addictive behavior. PMID:24358208

  3. A comparative antibody analysis of pannexin1 expression in four rat brain regions reveals varying subcellular localizations.

    PubMed

    Cone, Angela C; Ambrosi, Cinzia; Scemes, Eliana; Martone, Maryann E; Sosinsky, Gina E

    2013-01-01

    Pannexin1 (Panx1) channels release cytosolic ATP in response to signaling pathways. Panx1 is highly expressed in the central nervous system. We used four antibodies with different Panx1 anti-peptide epitopes to analyze four regions of rat brain. These antibodies labeled the same bands in Western blots and had highly similar patterns of immunofluorescence in tissue culture cells expressing Panx1, but Western blots of brain lysates from Panx1 knockout and control mice showed different banding patterns. Localizations of Panx1 in brain slices were generated using automated wide field mosaic confocal microscopy for imaging large regions of interest while retaining maximum resolution for examining cell populations and compartments. We compared Panx1 expression over the cerebellum, hippocampus with adjacent cortex, thalamus, and olfactory bulb. While Panx1 localizes to the same neuronal cell types, subcellular localizations differ. Two antibodies with epitopes against the intracellular loop and one against the carboxy terminus preferentially labeled cell bodies, while an antibody raised against an N-terminal peptide highlighted neuronal processes more than cell bodies. These labeling patterns may be a reflection of different cellular and subcellular localizations of full-length and/or modified Panx1 channels where each antibody is highlighting unique or differentially accessible Panx1 populations. However, we cannot rule out that one or more of these antibodies have specificity issues. All data associated with experiments from these four antibodies are presented in a manner that allows them to be compared and our claims thoroughly evaluated, rather than eliminating results that were questionable. Each antibody is given a unique identifier through the NIF Antibody Registry that can be used to track usage of individual antibodies across papers and all image and metadata are made available in the public repository, the Cell Centered Database, for on-line viewing, and

  4. A Comparative Antibody Analysis of Pannexin1 Expression in Four Rat Brain Regions Reveals Varying Subcellular Localizations

    PubMed Central

    Cone, Angela C.; Ambrosi, Cinzia; Scemes, Eliana; Martone, Maryann E.; Sosinsky, Gina E.

    2012-01-01

    Pannexin1 (Panx1) channels release cytosolic ATP in response to signaling pathways. Panx1 is highly expressed in the central nervous system. We used four antibodies with different Panx1 anti-peptide epitopes to analyze four regions of rat brain. These antibodies labeled the same bands in Western blots and had highly similar patterns of immunofluorescence in tissue culture cells expressing Panx1, but Western blots of brain lysates from Panx1 knockout and control mice showed different banding patterns. Localizations of Panx1 in brain slices were generated using automated wide field mosaic confocal microscopy for imaging large regions of interest while retaining maximum resolution for examining cell populations and compartments. We compared Panx1 expression over the cerebellum, hippocampus with adjacent cortex, thalamus, and olfactory bulb. While Panx1 localizes to the same neuronal cell types, subcellular localizations differ. Two antibodies with epitopes against the intracellular loop and one against the carboxy terminus preferentially labeled cell bodies, while an antibody raised against an N-terminal peptide highlighted neuronal processes more than cell bodies. These labeling patterns may be a reflection of different cellular and subcellular localizations of full-length and/or modified Panx1 channels where each antibody is highlighting unique or differentially accessible Panx1 populations. However, we cannot rule out that one or more of these antibodies have specificity issues. All data associated with experiments from these four antibodies are presented in a manner that allows them to be compared and our claims thoroughly evaluated, rather than eliminating results that were questionable. Each antibody is given a unique identifier through the NIF Antibody Registry that can be used to track usage of individual antibodies across papers and all image and metadata are made available in the public repository, the Cell Centered Database, for on-line viewing, and

  5. Missed appendicitis: did unexpected intraluminal densities play a role?

    PubMed

    Harper, Rachel; Friedman, Benjamin T; Strote, Jared

    2016-01-01

    A healthy 19-year-old boy presented to our emergency department with abdominal pain. His history, examination and laboratory evaluation raised concern for appendicitis. A CT study of the abdomen and pelvis was carried out by the radiologist and emergency physician and was notable only for a large amount of unexpected high-attenuation intraluminal material. With further history, this was thought to be most likely retained bismuth from over-the-counter medicine ingestion. The patient was discharged home without a diagnosis. Further review of the CT scan by a second radiologist revealed a concern for appendiceal enlargement and associated free fluid. The patient was called back for further evaluation and treatment and ultimately an appendectomy was performed. Physicians should be aware of the causes and impact of unexpected radiopaque intraluminal contents on radiological studies. Most commonly from ingested medicine, such findings can obscure mucosal details, mimic active bleeding or create a distraction from other abnormalities. PMID:27605197

  6. Genome-wide RNAi screens in human brain tumor isolates reveal a novel viability requirement for PHF5A

    PubMed Central

    Hubert, Christopher G.; Bradley, Robert K.; Ding, Yu; Toledo, Chad M.; Herman, Jacob; Skutt-Kakaria, Kyobi; Girard, Emily J.; Davison, Jerry; Berndt, Jason; Corrin, Philip; Hardcastle, Justin; Basom, Ryan; Delrow, Jeffery J.; Webb, Thomas; Pollard, Steven M.; Lee, Jeongwu; Olson, James M.; Paddison, Patrick J.

    2013-01-01

    To identify key regulators of human brain tumor maintenance and initiation, we performed multiple genome-wide RNAi screens in patient-derived glioblastoma multiforme (GBM) stem cells (GSCs). These screens identified the plant homeodomain (PHD)-finger domain protein PHF5A as differentially required for GSC expansion, as compared with untransformed neural stem cells (NSCs) and fibroblasts. Given PHF5A's known involvement in facilitating interactions between the U2 snRNP complex and ATP-dependent helicases, we examined cancer-specific roles in RNA splicing. We found that in GSCs, but not untransformed controls, PHF5A facilitates recognition of exons with unusual C-rich 3′ splice sites in thousands of essential genes. PHF5A knockdown in GSCs, but not untransformed NSCs, astrocytes, or fibroblasts, inhibited splicing of these genes, leading to cell cycle arrest and loss of viability. Notably, pharmacologic inhibition of U2 snRNP activity phenocopied PHF5A knockdown in GSCs and also in NSCs or fibroblasts overexpressing MYC. Furthermore, PHF5A inhibition compromised GSC tumor formation in vivo and inhibited growth of established GBM patient-derived xenograft tumors. Our results demonstrate a novel viability requirement for PHF5A to maintain proper exon recognition in brain tumor-initiating cells and may provide new inroads for novel anti-GBM therapeutic strategies. PMID:23651857

  7. Genome-wide RNAi screens in human brain tumor isolates reveal a novel viability requirement for PHF5A.

    PubMed

    Hubert, Christopher G; Bradley, Robert K; Ding, Yu; Toledo, Chad M; Herman, Jacob; Skutt-Kakaria, Kyobi; Girard, Emily J; Davison, Jerry; Berndt, Jason; Corrin, Philip; Hardcastle, Justin; Basom, Ryan; Delrow, Jeffery J; Webb, Thomas; Pollard, Steven M; Lee, Jeongwu; Olson, James M; Paddison, Patrick J

    2013-05-01

    To identify key regulators of human brain tumor maintenance and initiation, we performed multiple genome-wide RNAi screens in patient-derived glioblastoma multiforme (GBM) stem cells (GSCs). These screens identified the plant homeodomain (PHD)-finger domain protein PHF5A as differentially required for GSC expansion, as compared with untransformed neural stem cells (NSCs) and fibroblasts. Given PHF5A's known involvement in facilitating interactions between the U2 snRNP complex and ATP-dependent helicases, we examined cancer-specific roles in RNA splicing. We found that in GSCs, but not untransformed controls, PHF5A facilitates recognition of exons with unusual C-rich 3' splice sites in thousands of essential genes. PHF5A knockdown in GSCs, but not untransformed NSCs, astrocytes, or fibroblasts, inhibited splicing of these genes, leading to cell cycle arrest and loss of viability. Notably, pharmacologic inhibition of U2 snRNP activity phenocopied PHF5A knockdown in GSCs and also in NSCs or fibroblasts overexpressing MYC. Furthermore, PHF5A inhibition compromised GSC tumor formation in vivo and inhibited growth of established GBM patient-derived xenograft tumors. Our results demonstrate a novel viability requirement for PHF5A to maintain proper exon recognition in brain tumor-initiating cells and may provide new inroads for novel anti-GBM therapeutic strategies. PMID:23651857

  8. MRI/DTI of the Brain Stem Reveals Reversible and Irreversible Disruption of the Baroreflex Neural Circuits: Clinical Implications.

    PubMed

    Su, Chia-Hao; Tsai, Ching-Yi; Chang, Alice Y W; Chan, Julie Y H; Chan, Samuel H H

    2016-01-01

    Baroreflex is the physiological mechanism for the maintenance of blood pressure and heart rate. Impairment of baroreflex is not a disease per se. However, depending on severity, the eventuality of baroreflex dysfunction varies from inconvenience in daily existence to curtailment of mobility to death. Despite universal acceptance, neuronal traffic within the contemporary neural circuits during the execution of baroreflex has never been visualized. By enhancing signal detection and fine-tuning the scanning parameters, we have successfully implemented tractographic analysis of the medulla oblongata in mice that allowed for visualization of connectivity between key brain stem nuclei in the baroreflex circuits. When viewed in conjunction with radiotelemetric analysis of the baroreflex, we found that under pathophysiological conditions when the disrupted connectivity between key nuclei in the baroreflex circuits was reversible, the associated disease condition (e.g. neurogenic hypertension) was amenable to remedial measures. Nevertheless, fatality ensues under pathological conditions (e.g. hepatic encephalopathy) when the connectivity between key substrates in the baroreflex circuits was irreversibly severed. MRI/DTI also prompted partial re-wiring of the contemporary circuit for baroreflex-mediated sympathetic vasomotor tone, and unearthed an explanation for the time lapse between brain death and the inevitable asystole signifying cardiac death that follows. PMID:27162554

  9. Brain microstructure reveals early abnormalities more than two years prior to clinical progression from mild cognitive impairment to Alzheimer's disease.

    PubMed

    Douaud, Gwenaëlle; Menke, Ricarda A L; Gass, Achim; Monsch, Andreas U; Rao, Anil; Whitcher, Brandon; Zamboni, Giovanna; Matthews, Paul M; Sollberger, Marc; Smith, Stephen

    2013-01-30

    Diffusion imaging is a promising marker of microstructural damage in neurodegenerative disorders, but interpretation of its relationship with underlying neuropathology can be complex. Here, we examined both volumetric and brain microstructure abnormalities in 13 amnestic patients with mild cognitive impairment (MCI), who progressed to probable Alzheimer's disease (AD) no earlier than 2 years after baseline scanning, in order to focus on early, and hence more sensitive, imaging markers. We compared them to 22 stable amnestic MCI patients with similar cognitive performance and episodic memory impairment but who did not show progression of symptoms for at least 3 years. Significant group differences were mainly found in the volume and microstructure of the left hippocampus, while white matter group differences were also found in the body of the fornix, left fimbria, and superior longitudinal fasciculus (SLF). Diffusion index abnormalities in the SLF were the sign of a subtle microstructural injury not detected by standard atrophy measures in the corresponding gray matter regions. The microstructural measure obtained in the left hippocampus using diffusion imaging showed the most substantial differences between the two groups and was the best single predictor of future progression to AD. An optimal prediction model (91% accuracy, 85% sensitivity, 96% specificity) was obtained by combining MRI measures and CSF protein biomarkers. These results highlight the benefit of using the information of brain microstructural damage, in addition to traditional gray matter volume, to detect early, subtle abnormalities in MCI prior to clinical progression to probable AD and, in combination with CSF markers, to accurately predict such progression.

  10. Environmental changes in oxygen tension reveal ROS-dependent neurogenesis and regeneration in the adult newt brain

    PubMed Central

    Hameed, L Shahul; Berg, Daniel A; Belnoue, Laure; Jensen, Lasse D; Cao, Yihai; Simon, András

    2015-01-01

    Organisms need to adapt to the ecological constraints in their habitat. How specific processes reflect such adaptations are difficult to model experimentally. We tested whether environmental shifts in oxygen tension lead to events in the adult newt brain that share features with processes occurring during neuronal regeneration under normoxia. By experimental simulation of varying oxygen concentrations, we show that hypoxia followed by re-oxygenation lead to neuronal death and hallmarks of an injury response, including activation of neural stem cells ultimately leading to neurogenesis. Neural stem cells accumulate reactive oxygen species (ROS) during re-oxygenation and inhibition of ROS biosynthesis counteracts their proliferation as well as neurogenesis. Importantly, regeneration of dopamine neurons under normoxia also depends on ROS-production. These data demonstrate a role for ROS-production in neurogenesis in newts and suggest that this role may have been recruited to the capacity to replace lost neurons in the brain of an adult vertebrate. DOI: http://dx.doi.org/10.7554/eLife.08422.001 PMID:26485032

  11. Live imaging reveals a new role for the sigma-1 (σ1) receptor in allowing microglia to leave brain injuries.

    PubMed

    Moritz, Christian; Berardi, Francesco; Abate, Carmen; Peri, Francesca

    2015-03-30

    Microglial cells are responsible for clearing and maintaining the central nervous system (CNS) microenvironment. Upon brain damage, they move toward injuries to clear the area by engulfing dying neurons. However, in the context of many neurological disorders chronic microglial responses are responsible for neurodegeneration. Therefore, it is important to understand how these cells can be "switched-off" and regain their ramified state. Current research suggests that microglial inflammatory responses can be inhibited by sigma (σ) receptor activation. Here, we take advantage of the optical transparency of the zebrafish embryo to study the role of σ1 receptor in microglia in an intact living brain. By combining chemical approaches with real time imaging we found that treatment with PB190, a σ1 agonist, blocks microglial migration toward injuries leaving cellular baseline motility and the engulfment of apoptotic neurons unaffected. Most importantly, by taking a reverse genetic approach, we discovered that the role of σ1in vivo is to "switch-off" microglia after they responded to an injury allowing for these cells to leave the site of damage. This indicates that pharmacological manipulation of σ1 receptor modulates microglial responses providing new approaches to reduce the devastating impact that microglia have in neurodegenerative diseases.

  12. MRI/DTI of the Brain Stem Reveals Reversible and Irreversible Disruption of the Baroreflex Neural Circuits: Clinical Implications

    PubMed Central

    Su, Chia-Hao; Tsai, Ching-Yi; Chang, Alice Y.W.; Chan, Julie Y.H.; Chan, Samuel H.H.

    2016-01-01

    Baroreflex is the physiological mechanism for the maintenance of blood pressure and heart rate. Impairment of baroreflex is not a disease per se. However, depending on severity, the eventuality of baroreflex dysfunction varies from inconvenience in daily existence to curtailment of mobility to death. Despite universal acceptance, neuronal traffic within the contemporary neural circuits during the execution of baroreflex has never been visualized. By enhancing signal detection and fine-tuning the scanning parameters, we have successfully implemented tractographic analysis of the medulla oblongata in mice that allowed for visualization of connectivity between key brain stem nuclei in the baroreflex circuits. When viewed in conjunction with radiotelemetric analysis of the baroreflex, we found that under pathophysiological conditions when the disrupted connectivity between key nuclei in the baroreflex circuits was reversible, the associated disease condition (e.g. neurogenic hypertension) was amenable to remedial measures. Nevertheless, fatality ensues under pathological conditions (e.g. hepatic encephalopathy) when the connectivity between key substrates in the baroreflex circuits was irreversibly severed. MRI/DTI also prompted partial re-wiring of the contemporary circuit for baroreflex-mediated sympathetic vasomotor tone, and unearthed an explanation for the time lapse between brain death and the inevitable asystole signifying cardiac death that follows. PMID:27162554

  13. Central motor conduction in multiple sclerosis: evaluation of abnormalities revealed by transcutaneous magnetic stimulation of the brain.

    PubMed Central

    Ingram, D A; Thompson, A J; Swash, M

    1988-01-01

    Magnetic stimulation of the brain and spinal column was used to assess conduction in the descending central motor pathways controlling arm and leg muscles of 20 patients with multiple sclerosis, and 10 normal subjects. The multiple sclerosis patients had relapsing and remitting disease but all were ambulant and in stable clinical remission. Increased central motor conduction times (CMCTs), up to three times normal, were frequently encountered in multiple sclerosis patients and in leg muscles these correlated closely with clinical signs of upper motor neuron disturbance; in the upper limb muscles a higher proportion of subclinical lesions was present. Weak muscles were almost invariably associated with abnormal central conduction but increased CMCTs were also found for 52 of the 104 muscles with normal strength. CMCTs for lower limb muscles were directly related (p less than 0.005) to functional motor disability (Kurtzke and Ambulatory Index Scales). No patient developed clinical evidence of relapse during follow-up of at least 8 months. Magnetic brain stimulation is easy to perform, painless, and safe, and provides clinically relevant information in the diagnosis and monitoring of multiple sclerosis patients. PMID:2837538

  14. Body representations in the human brain revealed by kinesthetic illusions and their essential contributions to motor control and corporeal awareness.

    PubMed

    Naito, Eiichi; Morita, Tomoyo; Amemiya, Kaoru

    2016-03-01

    The human brain can generate a continuously changing postural model of our body. Somatic (proprioceptive) signals from skeletal muscles and joints contribute to the formation of the body representation. Recent neuroimaging studies of proprioceptive bodily illusions have elucidated the importance of three brain systems (motor network, specialized parietal systems, right inferior fronto-parietal network) in the formation of the human body representation. The motor network, especially the primary motor cortex, processes afferent input from skeletal muscles. Such information may contribute to the formation of kinematic/dynamic postural models of limbs, thereby enabling fast online feedback control. Distinct parietal regions appear to play specialized roles in the transformation/integration of information across different coordinate systems, which may subserve the adaptability and flexibility of the body representation. Finally, the right inferior fronto-parietal network, connected by the inferior branch of the superior longitudinal fasciculus, is consistently recruited when an individual experiences various types of bodily illusions and its possible roles relate to corporeal awareness, which is likely elicited through a series of neuronal processes of monitoring and accumulating bodily information and updating the body representation. Because this network is also recruited when identifying one's own features, the network activity could be a neuronal basis for self-consciousness.

  15. Royal jelly-like protein localization reveals differences in hypopharyngeal glands buildup and conserved expression pattern in brains of bumblebees and honeybees

    PubMed Central

    Albert, Štefan; Spaethe, Johannes; Grübel, Kornelia; Rössler, Wolfgang

    2014-01-01

    ABSTRACT Royal jelly proteins (MRJPs) of the honeybee bear several open questions. One of them is their expression in tissues other than the hypopharyngeal glands (HGs), the site of royal jelly production. The sole MRJP-like gene of the bumblebee, Bombus terrestris (BtRJPL), represents a pre-diversification stage of the MRJP gene evolution in bees. Here we investigate the expression of BtRJPL in the HGs and the brain of bumblebees. Comparison of the HGs of bumblebees and honeybees revealed striking differences in their morphology with respect to sex- and caste-specific appearance, number of cells per acinus, and filamentous actin (F-actin) rings. At the cellular level, we found a temporary F-actin-covered meshwork in the secretory cells, which suggests a role for actin in the biogenesis of the end apparatus in HGs. Using immunohistochemical localization, we show that BtRJPL is expressed in the bumblebee brain, predominantly in the Kenyon cells of the mushroom bodies, the site of sensory integration in insects, and in the optic lobes. Our data suggest that a dual gland-brain function preceded the multiplication of MRJPs in the honeybee lineage. In the course of the honeybee evolution, HGs dramatically changed their morphology in order to serve a food-producing function. PMID:24682007

  16. Genomics analysis of potassium channel genes in songbirds reveals molecular specializations of brain circuits for the maintenance and production of learned vocalizations

    PubMed Central

    2013-01-01

    Background A fundamental question in molecular neurobiology is how genes that determine basic neuronal properties shape the functional organization of brain circuits underlying complex learned behaviors. Given the growing availability of complete vertebrate genomes, comparative genomics represents a promising approach to address this question. Here we used genomics and molecular approaches to study how ion channel genes influence the properties of the brain circuitry that regulates birdsong, a learned vocal behavior with important similarities to human speech acquisition. We focused on potassium (K-)Channels, which are major determinants of neuronal cell excitability. Starting with the human gene set of K-Channels, we used cross-species mRNA/protein alignments, and syntenic analysis to define the full complement of orthologs, paralogs, allelic variants, as well as novel loci not previously predicted in the genome of zebra finch (Taeniopygia guttata). We also compared protein coding domains in chicken and zebra finch orthologs to identify genes under positive selective pressure, and those that contained lineage-specific insertions/deletions in functional domains. Finally, we conducted comprehensive in situ hybridizations to determine the extent of brain expression, and identify K-Channel gene enrichments in nuclei of the avian song system. Results We identified 107 K-Channel finch genes, including 6 novel genes common to non-mammalian vertebrate lineages. Twenty human genes are absent in songbirds, birds, or sauropsids, or unique to mammals, suggesting K-Channel properties may be lineage-specific. We also identified specific family members with insertions/deletions and/or high dN/dS ratios compared to chicken, a non-vocal learner. In situ hybridization revealed that while most K-Channel genes are broadly expressed in the brain, a subset is selectively expressed in song nuclei, representing molecular specializations of the vocal circuitry. Conclusions Together

  17. Pediatric Sudden Unexpected Death in Epilepsy: What Have we Learned from Animal and Human Studies, and Can we Prevent it?

    PubMed

    Holt, Rebecca L; Arehart, Eric; Hunanyan, Arsen; Fainberg, Nina A; Mikati, Mohamad A

    2016-05-01

    Several factors, such as epilepsy syndrome, poor compliance, and increased seizure frequency increase the risks of sudden unexpected death in epilepsy (SUDEP). Animal models have revealed that the mechanisms of SUDEP involve initially a primary event, often a seizure of sufficient type and severity, that occurs in a brain, which is vulnerable to SUDEP due to either genetic or antecedent factors. This primary event initiates a cascade of secondary events starting, as some models indicate, with cortical spreading depolarization that propagates to the brainstem where it results in autonomic dysfunction. Intrinsic abnormalities in brainstem serotonin, adenosine, sodium-postassium ATPase, and respiratory-control systems are also important. The tertiary event, which results from the above dysfunction, consists of either lethal central apnea, pulmonary edema, or arrhythmia. Currently, it is necessary to (1) continue researching SUDEP mechanisms, (2) work on reducing SUDEP risk factors, and (3) address the major need to counsel families about SUDEP. PMID:27544469

  18. Task-Related Edge Density (TED)—A New Method for Revealing Dynamic Network Formation in fMRI Data of the Human Brain

    PubMed Central

    Lohmann, Gabriele; Stelzer, Johannes; Zuber, Verena; Buschmann, Tilo; Margulies, Daniel; Bartels, Andreas; Scheffler, Klaus

    2016-01-01

    The formation of transient networks in response to external stimuli or as a reflection of internal cognitive processes is a hallmark of human brain function. However, its identification in fMRI data of the human brain is notoriously difficult. Here we propose a new method of fMRI data analysis that tackles this problem by considering large-scale, task-related synchronisation networks. Networks consist of nodes and edges connecting them, where nodes correspond to voxels in fMRI data, and the weight of an edge is determined via task-related changes in dynamic synchronisation between their respective times series. Based on these definitions, we developed a new data analysis algorithm that identifies edges that show differing levels of synchrony between two distinct task conditions and that occur in dense packs with similar characteristics. Hence, we call this approach “Task-related Edge Density” (TED). TED proved to be a very strong marker for dynamic network formation that easily lends itself to statistical analysis using large scale statistical inference. A major advantage of TED compared to other methods is that it does not depend on any specific hemodynamic response model, and it also does not require a presegmentation of the data for dimensionality reduction as it can handle large networks consisting of tens of thousands of voxels. We applied TED to fMRI data of a fingertapping and an emotion processing task provided by the Human Connectome Project. TED revealed network-based involvement of a large number of brain areas that evaded detection using traditional GLM-based analysis. We show that our proposed method provides an entirely new window into the immense complexity of human brain function. PMID:27341204

  19. Task-Related Edge Density (TED)-A New Method for Revealing Dynamic Network Formation in fMRI Data of the Human Brain.

    PubMed

    Lohmann, Gabriele; Stelzer, Johannes; Zuber, Verena; Buschmann, Tilo; Margulies, Daniel; Bartels, Andreas; Scheffler, Klaus

    2016-01-01

    The formation of transient networks in response to external stimuli or as a reflection of internal cognitive processes is a hallmark of human brain function. However, its identification in fMRI data of the human brain is notoriously difficult. Here we propose a new method of fMRI data analysis that tackles this problem by considering large-scale, task-related synchronisation networks. Networks consist of nodes and edges connecting them, where nodes correspond to voxels in fMRI data, and the weight of an edge is determined via task-related changes in dynamic synchronisation between their respective times series. Based on these definitions, we developed a new data analysis algorithm that identifies edges that show differing levels of synchrony between two distinct task conditions and that occur in dense packs with similar characteristics. Hence, we call this approach "Task-related Edge Density" (TED). TED proved to be a very strong marker for dynamic network formation that easily lends itself to statistical analysis using large scale statistical inference. A major advantage of TED compared to other methods is that it does not depend on any specific hemodynamic response model, and it also does not require a presegmentation of the data for dimensionality reduction as it can handle large networks consisting of tens of thousands of voxels. We applied TED to fMRI data of a fingertapping and an emotion processing task provided by the Human Connectome Project. TED revealed network-based involvement of a large number of brain areas that evaded detection using traditional GLM-based analysis. We show that our proposed method provides an entirely new window into the immense complexity of human brain function. PMID:27341204

  20. The age-related posterior-anterior shift as revealed by voxelwise analysis of functional brain networks

    PubMed Central

    McCarthy, Paul; Benuskova, Lubica; Franz, Elizabeth A.

    2014-01-01

    The posterior-anterior shift in aging (PASA) is a commonly observed phenomenon in functional neuroimaging studies of aging, characterized by age-related reductions in occipital activity alongside increases in frontal activity. In this work we have investigated the hypothesis as to whether the PASA is also manifested in functional brain network measures such as degree, clustering coefficient, path length and local efficiency. We have performed statistical analysis upon functional networks derived from a fMRI dataset containing data from healthy young, healthy aged, and aged individuals with very mild to mild Alzheimer's disease (AD). Analysis of both task based and resting state functional network properties has indicated that the PASA can also be characterized in terms of modulation of functional network properties, and that the onset of AD appears to accentuate this modulation. We also explore the effect of spatial normalization upon the results of our analysis. PMID:25426065

  1. Extensive Direct Subcortical Cerebellum-Basal Ganglia Connections in Human Brain as Revealed by Constrained Spherical Deconvolution Tractography

    PubMed Central

    Milardi, Demetrio; Arrigo, Alessandro; Anastasi, Giuseppe; Cacciola, Alberto; Marino, Silvia; Mormina, Enricomaria; Calamuneri, Alessandro; Bruschetta, Daniele; Cutroneo, Giuseppina; Trimarchi, Fabio; Quartarone, Angelo

    2016-01-01

    The connections between the cerebellum and basal ganglia were assumed to occur at the level of neocortex. However evidences from animal data have challenged this old perspective showing extensive subcortical pathways linking the cerebellum with the basal ganglia. Here we tested the hypothesis if these connections also exist between the cerebellum and basal ganglia in the human brain by using diffusion magnetic resonance imaging and tractography. Fifteen healthy subjects were analyzed by using constrained spherical deconvolution technique obtained with a 3T magnetic resonance imaging scanner. We found extensive connections running between the subthalamic nucleus and cerebellar cortex and, as novel result, we demonstrated a direct route linking the dentate nucleus to the internal globus pallidus as well as to the substantia nigra. These findings may open a new scenario on the interpretation of basal ganglia disorders. PMID:27047348

  2. Network Analysis of Genome-Wide Selective Constraint Reveals a Gene Network Active in Early Fetal Brain Intolerant of Mutation

    PubMed Central

    Choi, Jinmyung; Samocha, Kaitlin E.; Daly, Mark J.

    2016-01-01

    Using robust, integrated analysis of multiple genomic datasets, we show that genes depleted for non-synonymous de novo mutations form a subnetwork of 72 members under strong selective constraint. We further show this subnetwork is preferentially expressed in the early development of the human hippocampus and is enriched for genes mutated in neurological Mendelian disorders. We thus conclude that carefully orchestrated developmental processes are under strong constraint in early brain development, and perturbations caused by mutation have adverse outcomes subject to strong purifying selection. Our findings demonstrate that selective forces can act on groups of genes involved in the same process, supporting the notion that purifying selection can act coordinately on multiple genes. Our approach provides a statistically robust, interpretable way to identify the tissues and developmental times where groups of disease genes are active. PMID:27305007

  3. Brain structure. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq.

    PubMed

    Zeisel, Amit; Muñoz-Manchado, Ana B; Codeluppi, Simone; Lönnerberg, Peter; La Manno, Gioele; Juréus, Anna; Marques, Sueli; Munguba, Hermany; He, Liqun; Betsholtz, Christer; Rolny, Charlotte; Castelo-Branco, Gonçalo; Hjerling-Leffler, Jens; Linnarsson, Sten

    2015-03-01

    The mammalian cerebral cortex supports cognitive functions such as sensorimotor integration, memory, and social behaviors. Normal brain function relies on a diverse set of differentiated cell types, including neurons, glia, and vasculature. Here, we have used large-scale single-cell RNA sequencing (RNA-seq) to classify cells in the mouse somatosensory cortex and hippocampal CA1 region. We found 47 molecularly distinct subclasses, comprising all known major cell types in the cortex. We identified numerous marker genes, which allowed alignment with known cell types, morphology, and location. We found a layer I interneuron expressing Pax6 and a distinct postmitotic oligodendrocyte subclass marked by Itpr2. Across the diversity of cortical cell types, transcription factors formed a complex, layered regulatory code, suggesting a mechanism for the maintenance of adult cell type identity.

  4. Whole transcriptome sequencing of the aging rat brain reveals dynamic RNA changes in the dark matter of the genome.

    PubMed

    Wood, Shona H; Craig, Thomas; Li, Yang; Merry, Brian; de Magalhães, João Pedro

    2013-06-01

    Brain aging frequently underlies cognitive decline and is a major risk factor for neurodegenerative conditions. The exact molecular mechanisms underlying brain aging, however, remain unknown. Whole transcriptome sequencing provides unparalleled depth and sensitivity in gene expression profiling. It also allows non-coding RNA and splice variant detection/comparison across phenotypes. Using RNA-seq to sequence the cerebral cortex transcriptome in 6-, 12- and 28-month-old rats, age-related changes were studied. Protein-coding genes related to MHC II presentation and serotonin biosynthesis were differentially expressed (DE) in aging. Relative to protein-coding genes, more non-coding genes were DE over the three age-groups. RNA-seq quantifies not only levels of whole genes but also of their individual transcripts. Over the three age-groups, 136 transcripts were DE, 37 of which were so-called dark matter transcripts that do not map to known exons. Fourteen of these transcripts were identified as novel putative long non-coding RNAs. Evidence of isoform switching and changes in usage were found. Promoter and coding sequence usage were also altered, hinting of possible changes to mitochondrial transport within neurons. Therefore, in addition to changes in the expression of protein-coding genes, changes in transcript expression, isoform usage, and non-coding RNAs occur with age. This study demonstrates dynamic changes in RNA with age at various genomic levels, which may reflect changes in regulation of transcriptional networks and provides non-coding RNA gene candidates for further studies.

  5. Early event-related brain potentials and hemispheric asymmetries reveal mind-wandering while reading and predict comprehension.

    PubMed

    Broadway, James M; Franklin, Michael S; Schooler, Jonathan W

    2015-04-01

    The electroencephalogram (EEG) of mind-wandering (MW) was examined in event-related potentials (ERPs) and pre-stimulus alpha (8-12 Hz), over lateral-posterior sites of left and right brain hemispheres, while individuals read text passages. After controlling for individual differences in general intelligence (g), P1-asymmetry was greater (right-minus- left) and N1 amplitudes were more negative, when individuals were not MW (i.e., they were reading attentively). Approximately 82% of variance in reading comprehension was accounted for by the predictors: g, pre-stimulus alpha, left- and right-hemisphere P1, and left-hemisphere N1 (when individuals were not MW). Together, individual differences in MW-sensitive ERPs uniquely accounted for approximately 38% of the variance in reading comprehension, over and above prediction by g and pre-stimulus alpha. The within-person effect of MW on P1-asymmetry was estimated to account for an additional 4.6% of criterion variance. Implications for EEG/ERP research into attention, language processing, hemispheric asymmetries, and individual differences are discussed.

  6. Whole Exome Sequencing Reveals DYSF, FKTN, and ISPD Mutations in Congenital Muscular Dystrophy Without Brain or Eye Involvement

    PubMed Central

    Ceyhan-Birsoy, Ozge; Talim, Beril; Swanson, Lindsay C.; Karakaya, Mert; Graff, Michelle A.; Beggs, Alan H.; Topaloglu, Haluk

    2015-01-01

    Background Congenital muscular dystrophies (CMDs) are a genetically and clinically heterogeneous group of neuromuscular disorders. Several genes encoding extracellular matrix, nuclear envelope, sarcolemmal proteins and glycosylation enzymes have been implicated in CMDs. The large overlap of clinical presentations due to mutations in different genes poses a challenge for clinicians in determining disease etiology for each patient. Objective We investigated the use of whole exome sequencing (WES) in identifying the genetic cause of disease in 5 CMD patients from 3 families who presented with highly similar clinical features, including early-onset rapidly progressive weakness without brain or eye abnormalities. Methods Whole exome sequencing was performed on DNA from affected individuals. Potential functional impacts of mutations were investigated by immunostaining on available muscle biopsies. Results Pathogenic mutations in 3 different genes, DYSF, FKTN, and ISPD were identified in each family. Mutation in DYSF led to absence of dysferlin protein in patient muscle. Mutations in ISPD led to impaired ISDP function, as demonstrated by deficiency of α-dystroglycan glycosylation in patient muscle. Conclusions This study highlights the benefit of unbiased genomic approaches in molecular diagnosis of neuromuscular disorders with high clinical heterogeneity, such as the phenotypes observed in our patients. Our results suggest that dysferlin deficiency should be in the differential diagnosis of congenital and rapidly progressive muscular dystrophy, and therefore dysferlin antibody should be in the standard immunohistochemistry panel for muscle biopsies in cases with suspected CMD. PMID:25821721

  7. The distribution and morphological characteristics of cholinergic cells in the brain of monotremes as revealed by ChAT immunohistochemistry.

    PubMed

    Manger, P R; Fahringer, H M; Pettigrew, J D; Siegel, J M

    2002-01-01

    The present study employs choline acetyltransferase (ChAT) immunohistochemistry to identify the cholinergic neuronal population in the central nervous system of the monotremes. Two of the three extant species of monotreme were studied: the platypus (Ornithorhynchus anatinus) and the short-beaked echidna (Tachyglossus aculeatus). The distribution of cholinergic cells in the brain of these two species was virtually identical. Distinct groups of cholinergic cells were observed in the striatum, basal forebrain, habenula, pontomesencephalon, cranial nerve motor nuclei, and spinal cord. In contrast to other tetrapods studied with this technique, we failed to find evidence for cholinergic cells in the hypothalamus, the parabigeminal nucleus (or nucleus isthmus), or the cerebral cortex. The lack of hypothalamic cholinergic neurons creates a hiatus in the continuous antero-posterior aggregation of cholinergic neurons seen in other tetrapods. This hiatus might be functionally related to the phenomenology of monotreme sleep and to the ontogeny of sleep in mammals, as juvenile placental mammals exhibit a similar combination of sleep elements to that found in adult monotremes.

  8. Functionally Brain Network Connected to the Retrosplenial Cortex of Rats Revealed by 7T fMRI.

    PubMed

    Wang, Jingjuan; Nie, Binbin; Duan, Shaofeng; Zhu, Haitao; Liu, Hua; Shan, Baoci

    2016-01-01

    Functional networks are regarded as important mechanisms for increasing our understanding of brain function in healthy and diseased states, and increased interest has been focused on extending the study of functional networks to animal models because such models provide a functional understanding of disease progression, therapy and repair. In rodents, the retrosplenial cortex (RSC) is an important cortical region because it has a large size and presents transitional patterns of lamination between the neocortex and archicortex. In addition, a number of invasive studies have highlighted the importance of the RSC for many functions. However, the network based on the RSC in rodents remains unclear. Based on the critical importance of the RSC, we defined the bilateral RSCs as two regions of interest and estimated the network based on the RSC. The results showed that the related regions include the parietal association cortex, hippocampus, thalamus nucleus, midbrain structures, and hypothalamic mammillary bodies. Our findings indicate two possible major networks: a sensory-cognitive network that has a hub in the RSCs and processes sensory information, spatial learning, and episodic memory; and a second network that is involved in the regulation of visceral functions and arousal. In addition, functional asymmetry between the bilateral RSCs was observed.

  9. Brain potentials to native phoneme discrimination reveal the origin of individual differences in learning the sounds of a second language

    PubMed Central

    Díaz, Begoña; Baus, Cristina; Escera, Carles; Costa, Albert; Sebastián-Gallés, Núria

    2008-01-01

    Human beings differ in their ability to master the sounds of their second language (L2). Phonetic training studies have proposed that differences in phonetic learning stem from differences in psychoacoustic abilities rather than speech-specific capabilities. We aimed at finding the origin of individual differences in L2 phonetic acquisition in natural learning contexts. We consider two alternative explanations: a general psychoacoustic origin vs. a speech-specific one. For this purpose, event-related potentials (ERPs) were recorded from two groups of early, proficient Spanish-Catalan bilinguals who differed in their mastery of the Catalan (L2) phonetic contrast /e-ε/. Brain activity in response to acoustic change detection was recorded in three different conditions involving tones of different length (duration condition), frequency (frequency condition), and presentation order (pattern condition). In addition, neural correlates of speech change detection were also assessed for both native (/o/-/e/) and nonnative (/o/-/ö/) phonetic contrasts (speech condition). Participants' discrimination accuracy, reflected electrically as a mismatch negativity (MMN), was similar between the two groups of participants in the three acoustic conditions. Conversely, the MMN was reduced in poor perceivers (PP) when they were presented with speech sounds. Therefore, our results support a speech-specific origin of individual variability in L2 phonetic mastery. PMID:18852470

  10. NIRS-Based Hyperscanning Reveals Inter-brain Neural Synchronization during Cooperative Jenga Game with Face-to-Face Communication

    PubMed Central

    Liu, Ning; Mok, Charis; Witt, Emily E.; Pradhan, Anjali H.; Chen, Jingyuan E.; Reiss, Allan L.

    2016-01-01

    Functional near-infrared spectroscopy (fNIRS) is an increasingly popular technology for studying social cognition. In particular, fNIRS permits simultaneous measurement of hemodynamic activity in two or more individuals interacting in a naturalistic setting. Here, we used fNIRS hyperscanning to study social cognition and communication in human dyads engaged in cooperative and obstructive interaction while they played the game of Jenga™. Novel methods were developed to identify synchronized channels for each dyad and a structural node-based spatial registration approach was utilized for inter-dyad analyses. Strong inter-brain neural synchrony (INS) was observed in the posterior region of the right middle and superior frontal gyrus, in particular Brodmann area 8 (BA8), during cooperative and obstructive interaction. This synchrony was not observed during the parallel game play condition and the dialog section, suggesting that BA8 was involved in goal-oriented social interaction such as complex interactive movements and social decision-making. INS was also observed in the dorsomedial prefrontal cortex (dmPFC), in particular Brodmann 9, during cooperative interaction only. These additional findings suggest that BA9 may be particularly engaged when theory-of-mind (ToM) is required for cooperative social interaction. The new methods described here have the potential to significantly extend fNIRS applications to social cognitive research. PMID:27014019

  11. Functionally Brain Network Connected to the Retrosplenial Cortex of Rats Revealed by 7T fMRI

    PubMed Central

    Wang, Jingjuan; Nie, Binbin; Duan, Shaofeng; Zhu, Haitao; Liu, Hua; Shan, Baoci

    2016-01-01

    Functional networks are regarded as important mechanisms for increasing our understanding of brain function in healthy and diseased states, and increased interest has been focused on extending the study of functional networks to animal models because such models provide a functional understanding of disease progression, therapy and repair. In rodents, the retrosplenial cortex (RSC) is an important cortical region because it has a large size and presents transitional patterns of lamination between the neocortex and archicortex. In addition, a number of invasive studies have highlighted the importance of the RSC for many functions. However, the network based on the RSC in rodents remains unclear. Based on the critical importance of the RSC, we defined the bilateral RSCs as two regions of interest and estimated the network based on the RSC. The results showed that the related regions include the parietal association cortex, hippocampus, thalamus nucleus, midbrain structures, and hypothalamic mammillary bodies. Our findings indicate two possible major networks: a sensory-cognitive network that has a hub in the RSCs and processes sensory information, spatial learning, and episodic memory; and a second network that is involved in the regulation of visceral functions and arousal. In addition, functional asymmetry between the bilateral RSCs was observed. PMID:26745803

  12. Brain potentials to native phoneme discrimination reveal the origin of individual differences in learning the sounds of a second language.

    PubMed

    Díaz, Begoña; Baus, Cristina; Escera, Carles; Costa, Albert; Sebastián-Gallés, Núria

    2008-10-21

    Human beings differ in their ability to master the sounds of their second language (L2). Phonetic training studies have proposed that differences in phonetic learning stem from differences in psychoacoustic abilities rather than speech-specific capabilities. We aimed at finding the origin of individual differences in L2 phonetic acquisition in natural learning contexts. We consider two alternative explanations: a general psychoacoustic origin vs. a speech-specific one. For this purpose, event-related potentials (ERPs) were recorded from two groups of early, proficient Spanish-Catalan bilinguals who differed in their mastery of the Catalan (L2) phonetic contrast /e-epsilon/. Brain activity in response to acoustic change detection was recorded in three different conditions involving tones of different length (duration condition), frequency (frequency condition), and presentation order (pattern condition). In addition, neural correlates of speech change detection were also assessed for both native (/o/-/e/) and nonnative (/o/-/ö/) phonetic contrasts (speech condition). Participants' discrimination accuracy, reflected electrically as a mismatch negativity (MMN), was similar between the two groups of participants in the three acoustic conditions. Conversely, the MMN was reduced in poor perceivers (PP) when they were presented with speech sounds. Therefore, our results support a speech-specific origin of individual variability in L2 phonetic mastery.

  13. Event-related brain potentials reveal the time-course of language change detection in early bilinguals.

    PubMed

    Kuipers, Jan-Rouke; Thierry, Guillaume

    2010-05-01

    Using event-related brain potentials, we investigated the temporal course of language change detection in proficient bilinguals as compared to matched controls. Welsh-English bilingual participants and English controls were presented with a variant of the oddball paradigm involving picture-word pairs. The language of the spoken word was manipulated such that English was the frequent stimulus (75%) and Welsh the infrequent stimulus (25%). We also manipulated semantic relatedness between pictures and words, such that only half of the pictures were followed by a word that corresponded with the identity of the picture. The P2 wave was significantly modulated by language in the bilingual group only, suggesting that this group detected a language change as early as 200 ms after word onset. Monolinguals also reliably detected the language change, but at a later stage of semantic integration (N400 range), since Welsh words were perceived as meaningless. The early detection of a language change in bilinguals triggered stimulus re-evaluation mechanisms reflected by a significant P600 modulation by Welsh words. Furthermore, compared to English unrelated words, English words matching the picture identity elicited significantly greater P2 amplitudes in the bilingual group only, suggesting that proficient bilinguals validate an incoming word against their expectation based on the context. Overall, highly proficient bilinguals appear to detect language changes very early on during speech perception and to consciously monitor language changes when they occur.

  14. Functionally Brain Network Connected to the Retrosplenial Cortex of Rats Revealed by 7T fMRI.

    PubMed

    Wang, Jingjuan; Nie, Binbin; Duan, Shaofeng; Zhu, Haitao; Liu, Hua; Shan, Baoci

    2016-01-01

    Functional networks are regarded as important mechanisms for increasing our understanding of brain function in healthy and diseased states, and increased interest has been focused on extending the study of functional networks to animal models because such models provide a functional understanding of disease progression, therapy and repair. In rodents, the retrosplenial cortex (RSC) is an important cortical region because it has a large size and presents transitional patterns of lamination between the neocortex and archicortex. In addition, a number of invasive studies have highlighted the importance of the RSC for many functions. However, the network based on the RSC in rodents remains unclear. Based on the critical importance of the RSC, we defined the bilateral RSCs as two regions of interest and estimated the network based on the RSC. The results showed that the related regions include the parietal association cortex, hippocampus, thalamus nucleus, midbrain structures, and hypothalamic mammillary bodies. Our findings indicate two possible major networks: a sensory-cognitive network that has a hub in the RSCs and processes sensory information, spatial learning, and episodic memory; and a second network that is involved in the regulation of visceral functions and arousal. In addition, functional asymmetry between the bilateral RSCs was observed. PMID:26745803

  15. First- and second-order contrast sensitivity functions reveal disrupted visual processing following mild traumatic brain injury.

    PubMed

    Spiegel, Daniel P; Reynaud, Alexandre; Ruiz, Tatiana; Laguë-Beauvais, Maude; Hess, Robert; Farivar, Reza

    2016-05-01

    Vision is disrupted by traumatic brain injury (TBI), with vision-related complaints being amongst the most common in this population. Based on the neural responses of early visual cortical areas, injury to the visual cortex would be predicted to affect both 1(st) order and 2(nd) order contrast sensitivity functions (CSFs)-the height and/or the cut-off of the CSF are expected to be affected by TBI. Previous studies have reported disruptions only in 2(nd) order contrast sensitivity, but using a narrow range of parameters and divergent methodologies-no study has characterized the effect of TBI on the full CSF for both 1(st) and 2(nd) order stimuli. Such information is needed to properly understand the effect of TBI on contrast perception, which underlies all visual processing. Using a unified framework based on the quick contrast sensitivity function, we measured full CSFs for static and dynamic 1(st) and 2(nd) order stimuli. Our results provide a unique dataset showing alterations in sensitivity for both 1(st) and 2(nd) order visual stimuli. In particular, we show that TBI patients have increased sensitivity for 1(st) order motion stimuli and decreased sensitivity to orientation-defined and contrast-defined 2(nd) order stimuli. In addition, our data suggest that TBI patients' sensitivity for both 1(st) order stimuli and 2(nd) order contrast-defined stimuli is shifted towards higher spatial frequencies.

  16. Structural brain changes associated with antipsychotic treatment in schizophrenia as revealed by voxel-based morphometric MRI: an activation likelihood estimation meta-analysis

    PubMed Central

    2013-01-01

    Background The results of multiple studies on the association between antipsychotic use and structural brain changes in schizophrenia have been assessed only in qualitative literature reviews to date. We aimed to perform a meta-analysis of voxel-based morphometry (VBM) studies on this association to quantitatively synthesize the findings of these studies. Methods A systematic computerized literature search was carried out through MEDLINE/PubMed, EMBASE, ISI Web of Science, SCOPUS and PsycINFO databases aiming to identify all VBM studies addressing this question and meeting predetermined inclusion criteria. All studies reporting coordinates representing foci of structural brain changes associated with antipsychotic use were meta-analyzed by using the activation likelihood estimation technique, currently the most sophisticated and best-validated tool for voxel-wise meta-analysis of neuroimaging studies. Results Ten studies (five cross-sectional and five longitudinal) met the inclusion criteria and comprised a total of 548 individuals (298 patients on antipsychotic drugs and 250 controls). Depending on the methodologies of the selected studies, the control groups included healthy subjects, drug-free patients, or the same patients evaluated repeatedly in longitudinal comparisons (i.e., serving as their own controls). A total of 102 foci associated with structural alterations were retrieved. The meta-analysis revealed seven clusters of areas with consistent structural brain changes in patients on antipsychotics compared to controls. The seven clusters included four areas of relative volumetric decrease in the left lateral temporal cortex [Brodmann area (BA) 20], left inferior frontal gyrus (BA 44), superior frontal gyrus extending to the left middle frontal gyrus (BA 6), and right rectal gyrus (BA 11), and three areas of relative volumetric increase in the left dorsal anterior cingulate cortex (BA 24), left ventral anterior cingulate cortex (BA 24) and right putamen

  17. Asynchronous presentation of global and local information reveals effects of attention on brain electrical activity specific to each level.

    PubMed

    Iglesias-Fuster, Jorge; Santos-Rodríguez, Yusniel; Trujillo-Barreto, Nelson; Valdés-Sosa, Mitchell J

    2014-01-01

    The neural basis of selective attention within hierarchically organized Navon figures has been extensively studied with event related potentials (ERPs), by contrasting responses obtained when attending the global and the local echelons. The findings are inherently ambiguous because both levels are always presented together. Thus, only a mixture of the brain responses to two levels can be observed. Here, we use a method that allows unveiling of global and local letters at distinct times, enabling estimation of separate ERPs related to each level. Two interspersed oddball streams were presented, each using letters from one level and comprised of frequent distracters and rare targets. Previous work and our Experiment 1 show that it is difficult to divide attention between two such streams of stimuli. ERP recording in Experiment 2 evinced an early selection negativity (SN, with latencies to the 50% area of about 266 ms for global distracters and 276 ms for local distracters) that was larger for attended relative to unattended distracters. The SN was larger over right posterior occipito-temporal derivations for global stimuli and over left posterior occipito-temporal derivations for local stimuli (although the latter was less strongly lateralized). A discrimination negativity (DN, accompanied by a P3b) was larger for attended targets relative to attended distracters, with latencies to the 50% area of about 316 ms for global stimuli and 301 ms for local stimuli, which presented a similar distribution for both levels over left temporo-parietal electrodes. The two negativities apparently index successive stages in the processing of a selected level within a compound figure. By resolving the ambiguity of traditional designs, our method allowed us to observe the effects of attention for each hierarchical level on its own.

  18. Sexually Dimorphic Gene Expression Associated with Growth and Reproduction of Tongue Sole (Cynoglossus semilaevis) Revealed by Brain Transcriptome Analysis.

    PubMed

    Wang, Pingping; Zheng, Min; Liu, Jian; Liu, Yongzhuang; Lu, Jianguo; Sun, Xiaowen

    2016-08-26

    In this study, we performed a comprehensive analysis of the transcriptome of one- and two-year-old male and female brains of Cynoglossus semilaevis by high-throughput Illumina sequencing. A total of 77,066 transcripts, corresponding to 21,475 unigenes, were obtained with a N50 value of 4349 bp. Of these unigenes, 33 genes were found to have significant differential expression and potentially associated with growth, from which 18 genes were down-regulated and 12 genes were up-regulated in two-year-old males, most of these genes had no significant differences in expression among one-year-old males and females and two-year-old females. A similar analysis was conducted to look for genes associated with reproduction; 25 genes were identified, among them, five genes were found to be down regulated and 20 genes up regulated in two-year-old males, again, most of the genes had no significant expression differences among the other three. The performance of up regulated genes in Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was significantly different between two-year-old males and females. Males had a high gene expression in genetic information processing, while female's highly expressed genes were mainly enriched on organismal systems. Our work identified a set of sex-biased genes potentially associated with growth and reproduction that might be the candidate factors affecting sexual dimorphism of tongue sole, laying the foundation to understand the complex process of sex determination of this economic valuable species.

  19. Brain-derived neurotrophic factor increases inhibitory synapses, revealed in solitary neurons cultured from rat visual cortex.

    PubMed

    Palizvan, M R; Sohya, K; Kohara, K; Maruyama, A; Yasuda, H; Kimura, F; Tsumoto, T

    2004-01-01

    To elucidate chronic actions of brain-derived neurotrophic factor (BDNF) on GABAergic synapses, we examined effects of a long-term application of BDNF for 10-15 days on autapses (synapses) of solitary GABAergic neurons cultured from rat visual cortex. Solitary neuron preparations were used to exclude a possible contamination of BDNF actions on excitatory neurons in dissociated neuron culture or slice preparations. Neurons were confirmed to be GABAergic pharmacologically with bicuculline, a selective antagonist for GABAA receptors and immunocytochemically with antibody against glutamic acid decarboxylase 65, a GABA synthesizing enzyme. To evaluate GABAergic synaptic function, evoked and/or miniature inhibitory postsynaptic currents (IPSCs) were recorded in the whole-cell voltage-clamp mode. The treatment with BDNF at a concentration of 100 ng/ml enhanced the amplitude of evoked IPSCs and the frequency of miniature IPSCs. In contrast, BDNF did not have a detectable effect on the amplitude of miniature IPSCs and the paired pulse ratio of IPSCs evoked by two, successive activations. To evaluate morphological changes, neurons were immunocytochemically stained with antibodies against microtubule-associated protein 2, to visualize somatodendritic region and synapsin I, to visualize presynaptic sites. The quantitative analysis indicated that BDNF increased the area of soma, the numbers of primary dendrites and dendritic branching points, the total length of dendrites and the number of synaptic sites. Such an action of BDNF was seen in both subgroups of GABAergic neurons, parvalbumin-positive and -negative neurons. To visualize functionally active presynaptic sites, neurons were stained with a styryl dye, FM1-43. BDNF increased the number of stained sites that was correlated with the frequency of miniature IPSCs. These results suggest that the chronic treatment with BDNF promotes dendritic and synaptic development of GABAergic neurons in visual cortex.

  20. Asynchronous presentation of global and local information reveals effects of attention on brain electrical activity specific to each level

    PubMed Central

    Iglesias-Fuster, Jorge; Santos-Rodríguez, Yusniel; Trujillo-Barreto, Nelson; Valdés-Sosa, Mitchell J.

    2015-01-01

    The neural basis of selective attention within hierarchically organized Navon figures has been extensively studied with event related potentials (ERPs), by contrasting responses obtained when attending the global and the local echelons. The findings are inherently ambiguous because both levels are always presented together. Thus, only a mixture of the brain responses to two levels can be observed. Here, we use a method that allows unveiling of global and local letters at distinct times, enabling estimation of separate ERPs related to each level. Two interspersed oddball streams were presented, each using letters from one level and comprised of frequent distracters and rare targets. Previous work and our Experiment 1 show that it is difficult to divide attention between two such streams of stimuli. ERP recording in Experiment 2 evinced an early selection negativity (SN, with latencies to the 50% area of about 266 ms for global distracters and 276 ms for local distracters) that was larger for attended relative to unattended distracters. The SN was larger over right posterior occipito-temporal derivations for global stimuli and over left posterior occipito-temporal derivations for local stimuli (although the latter was less strongly lateralized). A discrimination negativity (DN, accompanied by a P3b) was larger for attended targets relative to attended distracters, with latencies to the 50% area of about 316 ms for global stimuli and 301 ms for local stimuli, which presented a similar distribution for both levels over left temporo-parietal electrodes. The two negativities apparently index successive stages in the processing of a selected level within a compound figure. By resolving the ambiguity of traditional designs, our method allowed us to observe the effects of attention for each hierarchical level on its own. PMID:25628590

  1. Sexually Dimorphic Gene Expression Associated with Growth and Reproduction of Tongue Sole (Cynoglossus semilaevis) Revealed by Brain Transcriptome Analysis

    PubMed Central

    Wang, Pingping; Zheng, Min; Liu, Jian; Liu, Yongzhuang; Lu, Jianguo; Sun, Xiaowen

    2016-01-01

    In this study, we performed a comprehensive analysis of the transcriptome of one- and two-year-old male and female brains of Cynoglossus semilaevis by high-throughput Illumina sequencing. A total of 77,066 transcripts, corresponding to 21,475 unigenes, were obtained with a N50 value of 4349 bp. Of these unigenes, 33 genes were found to have significant differential expression and potentially associated with growth, from which 18 genes were down-regulated and 12 genes were up-regulated in two-year-old males, most of these genes had no significant differences in expression among one-year-old males and females and two-year-old females. A similar analysis was conducted to look for genes associated with reproduction; 25 genes were identified, among them, five genes were found to be down regulated and 20 genes up regulated in two-year-old males, again, most of the genes had no significant expression differences among the other three. The performance of up regulated genes in Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was significantly different between two-year-old males and females. Males had a high gene expression in genetic information processing, while female’s highly expressed genes were mainly enriched on organismal systems. Our work identified a set of sex-biased genes potentially associated with growth and reproduction that might be the candidate factors affecting sexual dimorphism of tongue sole, laying the foundation to understand the complex process of sex determination of this economic valuable species. PMID:27571066

  2. Sexually Dimorphic Gene Expression Associated with Growth and Reproduction of Tongue Sole (Cynoglossus semilaevis) Revealed by Brain Transcriptome Analysis.

    PubMed

    Wang, Pingping; Zheng, Min; Liu, Jian; Liu, Yongzhuang; Lu, Jianguo; Sun, Xiaowen

    2016-01-01

    In this study, we performed a comprehensive analysis of the transcriptome of one- and two-year-old male and female brains of Cynoglossus semilaevis by high-throughput Illumina sequencing. A total of 77,066 transcripts, corresponding to 21,475 unigenes, were obtained with a N50 value of 4349 bp. Of these unigenes, 33 genes were found to have significant differential expression and potentially associated with growth, from which 18 genes were down-regulated and 12 genes were up-regulated in two-year-old males, most of these genes had no significant differences in expression among one-year-old males and females and two-year-old females. A similar analysis was conducted to look for genes associated with reproduction; 25 genes were identified, among them, five genes were found to be down regulated and 20 genes up regulated in two-year-old males, again, most of the genes had no significant expression differences among the other three. The performance of up regulated genes in Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was significantly different between two-year-old males and females. Males had a high gene expression in genetic information processing, while female's highly expressed genes were mainly enriched on organismal systems. Our work identified a set of sex-biased genes potentially associated with growth and reproduction that might be the candidate factors affecting sexual dimorphism of tongue sole, laying the foundation to understand the complex process of sex determination of this economic valuable species. PMID:27571066

  3. Frequency specific interactions of MEG resting state activity within and across brain networks as revealed by the multivariate interaction measure.

    PubMed

    Marzetti, L; Della Penna, S; Snyder, A Z; Pizzella, V; Nolte, G; de Pasquale, F; Romani, G L; Corbetta, M

    2013-10-01

    Resting state networks (RSNs) are sets of brain regions exhibiting temporally coherent activity fluctuations in the absence of imposed task structure. RSNs have been extensively studied with fMRI in the infra-slow frequency range (nominally <10(-1)Hz). The topography of fMRI RSNs reflects stationary temporal correlation over minutes. However, neuronal communication occurs on a much faster time scale, at frequencies nominally in the range of 10(0)-10(2)Hz. We examined phase-shifted interactions in the delta (2-3.5 Hz), theta (4-7 Hz), alpha (8-12 Hz) and beta (13-30 Hz) frequency bands of resting-state source space MEG signals. These analyses were conducted between nodes of the dorsal attention network (DAN), one of the most robust RSNs, and between the DAN and other networks. Phase shifted interactions were mapped by the multivariate interaction measure (MIM), a measure of true interaction constructed from the maximization of imaginary coherency in the virtual channels comprised of voxel signals in source space. Non-zero-phase interactions occurred between homologous left and right hemisphere regions of the DAN in the delta and alpha frequency bands. Even stronger non-zero-phase interactions were detected between networks. Visual regions bilaterally showed phase-shifted interactions in the alpha band with regions of the DAN. Bilateral somatomotor regions interacted with DAN nodes in the beta band. These results demonstrate the existence of consistent, frequency specific phase-shifted interactions on a millisecond time scale between cortical regions within RSN as well as across RSNs. PMID:23631996

  4. Abnormal brain activation of adolescent internet addict in a ball-throwing animation task: possible neural correlates of disembodiment revealed by fMRI.

    PubMed

    Kim, Yeoung-Rang; Son, Jung-Woo; Lee, Sang-Ick; Shin, Chul-Jin; Kim, Sie-Kyeong; Ju, Gawon; Choi, Won-Hee; Oh, Jong-Hyun; Lee, Seungbok; Jo, Seongwoo; Ha, Tae Hyon

    2012-10-01

    While adolescent internet addicts are immersed in cyberspace, they are easily able to experience 'disembodied state'. The purposes of this study were to investigate the difference of brain activity between adolescent internet addicts and normal adolescents in a state of disembodiment, and to find the correlation between the activities of disembodiment-related areas and the behavioral characteristics related to internet addiction. The fMRI images were taken while the addiction group (N=17) and the control group (N=17) were asked to perform the task composed with ball-throwing animations. The task reflected on either self-agency about ball-throwing or location of a ball. And each block was shown with either different (Changing View) or same animations (Fixed View). The disembodiment-related condition was the interaction between Agency Task and Changing View. Within-group analyses revealed that the addiction group exhibited higher activation in the thalamus, bilateral precentral area, bilateral middle frontal area, and the area around the right temporo-parietal junction. And between-group analyses showed that the addiction group exhibited higher activation in the area near the left temporo-parieto-occipital junction, right parahippocampal area, and other areas than the control group. Finally, the duration of internet use was significantly correlated with the activity of posterior area of left middle temporal gyrus in the addiction group. These results show that the disembodiment-related activation of the brain is easily manifested in adolescent internet addicts. Internet addiction of adolescents could be significantly unfavorable for their brain development related with identity formation. PMID:22687465

  5. The human brain and face: mechanisms of cranial, neurological and facial development revealed through malformations of holoprosencephaly, cyclopia and aberrations in chromosome 18.

    PubMed

    Gondré-Lewis, Marjorie C; Gboluaje, Temitayo; Reid, Shaina N; Lin, Stephen; Wang, Paul; Green, William; Diogo, Rui; Fidélia-Lambert, Marie N; Herman, Mary M

    2015-09-01

    The study of inborn genetic errors can lend insight into mechanisms of normal human development and congenital malformations. Here, we present the first detailed comparison of cranial and neuro pathology in two exceedingly rare human individuals with cyclopia and alobar holoprosencephaly (HPE) in the presence and absence of aberrant chromosome 18 (aCh18). The aCh18 fetus contained one normal Ch18 and one with a pseudo-isodicentric duplication of chromosome 18q and partial deletion of 18p from 18p11.31 where the HPE gene, TGIF, resides, to the p terminus. In addition to synophthalmia, the aCh18 cyclopic malformations included a failure of induction of most of the telencephalon - closely approximating anencephaly, unchecked development of brain stem structures, near absence of the sphenoid bone and a malformed neurocranium and viscerocranium that constitute the median face. Although there was complete erasure of the olfactory and superior nasal structures, rudiments of nasal structures derived from the maxillary bone were evident, but with absent pharyngeal structures. The second non-aCh18 cyclopic fetus was initially classified as a true Cyclops, as it appeared to have a proboscis and one median eye with a single iris, but further analysis revealed two eye globes as expected for synophthalmic cyclopia. Furthermore, the proboscis was associated with the medial ethmoid ridge, consistent with an incomplete induction of these nasal structures, even as the nasal septum and paranasal sinuses were apparently developed. An important conclusion of this study is that it is the brain that predicts the overall configuration of the face, due to its influence on the development of surrounding skeletal structures. The present data using a combination of macroscopic, computed tomography (CT) and magnetic resonance imaging (MRI) techniques provide an unparalleled analysis on the extent of the effects of median defects, and insight into normal development and patterning of the brain

  6. The human brain and face: mechanisms of cranial, neurological and facial development revealed through malformations of holoprosencephaly, cyclopia and aberrations in chromosome 18

    PubMed Central

    Gondré-Lewis, Marjorie C.; Gboluaje, Temitayo; Reid, Shaina N.; Lin, Stephen; Wang, Paul; Green, William; Diogo, Rui; Fidélia-Lambert, Marie N.; Herman, Mary M.

    2016-01-01

    The study of inborn genetic errors can lend insight into mechanisms of normal human development and congenital malformations. Here, we present the first detailed comparison of cranial and neuro pathology in two exceedingly rare human individuals with cyclopia and alobar holoprosencephaly (HPE) in the presence and absence of aberrant chromosome 18 (aCh18). The aCh18 fetus contained one normal Ch18 and one with a pseudo-isodicentric duplication of chromosome 18q and partial deletion of 18p from 18p11.31 where the HPE gene, TGIF, resides, to the p terminus. In addition to synophthalmia, the aCh18 cyclopic malformations included a failure of induction of most of the telencephalon – closely approximating anencephaly, unchecked development of brain stem structures, near absence of the sphenoid bone and a malformed neurocranium and viscerocranium that constitute the median face. Although there was complete erasure of the olfactory and superior nasal structures, rudiments of nasal structures derived from the maxillary bone were evident, but with absent pharyngeal structures. The second non-aCh18 cyclopic fetus was initially classified as a true Cyclops, as it appeared to have a proboscis and one median eye with a single iris, but further analysis revealed two eye globes as expected for synophthalmic cyclopia. Furthermore, the proboscis was associated with the medial ethmoid ridge, consistent with an incomplete induction of these nasal structures, even as the nasal septum and paranasal sinuses were apparently developed. An important conclusion of this study is that it is the brain that predicts the overall configuration of the face, due to its influence on the development of surrounding skeletal structures. The present data using a combination of macroscopic, computed tomography (CT) and magnetic resonance imaging (MRI) techniques provide an unparalleled analysis on the extent of the effects of median defects, and insight into normal development and patterning of the

  7. Increase of 20-HETE synthase after brain ischemia in rats revealed by PET study with 11C-labeled 20-HETE synthase-specific inhibitor

    PubMed Central

    Kawasaki, Toshiyuki; Marumo, Toshiyuki; Shirakami, Keiko; Mori, Tomoko; Doi, Hisashi; Suzuki, Masaaki; Watanabe, Yasuyoshi; Chaki, Shigeyuki; Nakazato, Atsuro; Ago, Yukio; Hashimoto, Hitoshi; Matsuda, Toshio; Baba, Akemichi; Onoe, Hirotaka

    2012-01-01

    20-Hydroxyeicosatetraenoic acid (20-HETE), an arachidonic acid metabolite known to be produced after cerebral ischemia, has been implicated in ischemic and reperfusion injury by mediating vasoconstriction. To develop a positron emission tomography (PET) probe for 20-HETE synthase imaging, which might be useful for monitoring vasoconstrictive processes in patients with brain ischemia, we synthesized a 11C-labeled specific 20-HETE synthase inhibitor, N′(4-dimethylaminohexyloxy)phenyl imidazole ([11C]TROA). Autoradiographic study showed that [11C]TROA has high-specific binding in the kidney and liver consistent with the previously reported distribution of 20-HETE synthase. Using transient middle cerebral artery occlusion in rats, PET study showed significant increases in the binding of [11C]TROA in the ipsilateral hemisphere of rat brains after 7 and 10 days, which was blocked by co-injection of excess amounts of TROA (10 mg/kg). The increased [11C]TROA binding on the ipsilateral side returned to basal levels within 14 days. In addition, quantitative real-time PCR revealed that increased expression of 20-HETE synthase was only shown on the ipsilateral side on day 7. These results indicate that [11C]TROA might be a useful PET probe for imaging of 20-HETE synthase in patients with cerebral ischemia. PMID:22669478

  8. An Unexpected Influence on a Quadratic

    ERIC Educational Resources Information Center

    Davis, Jon D.

    2013-01-01

    Using technology to explore the coefficients of a quadratic equation can lead to an unexpected result. This article describes an investigation that involves sliders and dynamically linked representations. It guides students to notice the effect that the parameter "a" has on the graphical representation of a quadratic function in the form…

  9. Some Unexpected Results Using Computer Algebra Systems.

    ERIC Educational Resources Information Center

    Alonso, Felix; Garcia, Alfonsa; Garcia, Francisco; Hoya, Sara; Rodriguez, Gerardo; de la Villa, Agustin

    2001-01-01

    Shows how teachers can often use unexpected outputs from Computer Algebra Systems (CAS) to reinforce concepts and to show students the importance of thinking about how they use the software and reflecting on their results. Presents different examples where DERIVE, MAPLE, or Mathematica does not work as expected and suggests how to use them as a…

  10. Orchestrating Proactive and Reactive Mechanisms for Filtering Distracting Information: Brain-Behavior Relationships Revealed by a Mixed-Design fMRI Study.

    PubMed

    Marini, Francesco; Demeter, Elise; Roberts, Kenneth C; Chelazzi, Leonardo; Woldorff, Marty G

    2016-01-20

    Given the information overload often imparted to human cognitive-processing systems, suppression of irrelevant and distracting information is essential for successful behavior. Using a hybrid block/event-related fMRI design, we characterized proactive and reactive brain mechanisms for filtering distracting stimuli. Participants performed a flanker task, discriminating the direction of a target arrow in the presence versus absence of congruent or incongruent flanking distracting arrows during either Pure blocks (distracters always absent) or Mixed blocks (distracters on 80% of trials). Each Mixed block had either 20% or 60% incongruent trials. Activations in the dorsal frontoparietal attention network during Mixed versus Pure blocks evidenced proactive (blockwise) recruitment of a distraction-filtering mechanism. Sustained activations in right middle frontal gyrus during 60% Incongruent blocks correlated positively with behavioral indices of distraction-filtering (slowing when distracters might occur) and negatively with distraction-related behavioral costs (incongruent vs congruent trials), suggesting a role in coordinating proactive filtering of potential distracters. Event-related analyses showed that incongruent trials elicited greater reactive activations in 20% (vs 60%) Incongruent blocks for counteracting distraction and conflict, including in the insula and anterior cingulate. Context-related effects in occipitoparietal cortex consisted of greater target-evoked activations for distracter-absent trials (central-target-only) in Mixed versus Pure blocks, suggesting enhanced attentional engagement. Functional-localizer analyses in V1/V2/V3 revealed less distracter-processing activity in 60% (vs 20%) Incongruent blocks, presumably reflecting tonic suppression by proactive filtering mechanisms. These results delineate brain mechanisms underlying proactive and reactive filtering of distraction and conflict, and how they are orchestrated depending on distraction

  11. Orchestrating Proactive and Reactive Mechanisms for Filtering Distracting Information: Brain-Behavior Relationships Revealed by a Mixed-Design fMRI Study.

    PubMed

    Marini, Francesco; Demeter, Elise; Roberts, Kenneth C; Chelazzi, Leonardo; Woldorff, Marty G

    2016-01-20

    Given the information overload often imparted to human cognitive-processing systems, suppression of irrelevant and distracting information is essential for successful behavior. Using a hybrid block/event-related fMRI design, we characterized proactive and reactive brain mechanisms for filtering distracting stimuli. Participants performed a flanker task, discriminating the direction of a target arrow in the presence versus absence of congruent or incongruent flanking distracting arrows during either Pure blocks (distracters always absent) or Mixed blocks (distracters on 80% of trials). Each Mixed block had either 20% or 60% incongruent trials. Activations in the dorsal frontoparietal attention network during Mixed versus Pure blocks evidenced proactive (blockwise) recruitment of a distraction-filtering mechanism. Sustained activations in right middle frontal gyrus during 60% Incongruent blocks correlated positively with behavioral indices of distraction-filtering (slowing when distracters might occur) and negatively with distraction-related behavioral costs (incongruent vs congruent trials), suggesting a role in coordinating proactive filtering of potential distracters. Event-related analyses showed that incongruent trials elicited greater reactive activations in 20% (vs 60%) Incongruent blocks for counteracting distraction and conflict, including in the insula and anterior cingulate. Context-related effects in occipitoparietal cortex consisted of greater target-evoked activations for distracter-absent trials (central-target-only) in Mixed versus Pure blocks, suggesting enhanced attentional engagement. Functional-localizer analyses in V1/V2/V3 revealed less distracter-processing activity in 60% (vs 20%) Incongruent blocks, presumably reflecting tonic suppression by proactive filtering mechanisms. These results delineate brain mechanisms underlying proactive and reactive filtering of distraction and conflict, and how they are orchestrated depending on distraction

  12. Voice-sensitive regions in the dog and human brain are revealed by comparative fMRI.

    PubMed

    Andics, Attila; Gácsi, Márta; Faragó, Tamás; Kis, Anna; Miklósi, Adám

    2014-03-01

    During the approximately 18-32 thousand years of domestication, dogs and humans have shared a similar social environment. Dog and human vocalizations are thus familiar and relevant to both species, although they belong to evolutionarily distant taxa, as their lineages split approximately 90-100 million years ago. In this first comparative neuroimaging study of a nonprimate and a primate species, we made use of this special combination of shared environment and evolutionary distance. We presented dogs and humans with the same set of vocal and nonvocal stimuli to search for functionally analogous voice-sensitive cortical regions. We demonstrate that voice areas exist in dogs and that they show a similar pattern to anterior temporal voice areas in humans. Our findings also reveal that sensitivity to vocal emotional valence cues engages similarly located nonprimary auditory regions in dogs and humans. Although parallel evolution cannot be excluded, our findings suggest that voice areas may have a more ancient evolutionary origin than previously known. PMID:24560578

  13. Abnormal Frontostriatal Activity During Unexpected Reward Receipt in Depression and Schizophrenia: Relationship to Anhedonia

    PubMed Central

    Segarra, Nuria; Metastasio, Antonio; Ziauddeen, Hisham; Spencer, Jennifer; Reinders, Niels R; Dudas, Robert B; Arrondo, Gonzalo; Robbins, Trevor W; Clark, Luke; Fletcher, Paul C; Murray, Graham K

    2016-01-01

    Alterations in reward processes may underlie motivational and anhedonic symptoms in depression and schizophrenia. However it remains unclear whether these alterations are disorder-specific or shared, and whether they clearly relate to symptom generation or not. We studied brain responses to unexpected rewards during a simulated slot-machine game in 24 patients with depression, 21 patients with schizophrenia, and 21 healthy controls using functional magnetic resonance imaging. We investigated relationships between brain activation, task-related motivation, and questionnaire rated anhedonia. There was reduced activation in the orbitofrontal cortex, ventral striatum, inferior temporal gyrus, and occipital cortex in both depression and schizophrenia in comparison with healthy participants during receipt of unexpected reward. In the medial prefrontal cortex both patient groups showed reduced activation, with activation significantly more abnormal in schizophrenia than depression. Anterior cingulate and medial frontal cortical activation predicted task-related motivation, which in turn predicted anhedonia severity in schizophrenia. Our findings provide evidence for overlapping hypofunction in ventral striatal and orbitofrontal regions in depression and schizophrenia during unexpected reward receipt, and for a relationship between unexpected reward processing in the medial prefrontal cortex and the generation of motivational states. PMID:26708106

  14. Abnormal Frontostriatal Activity During Unexpected Reward Receipt in Depression and Schizophrenia: Relationship to Anhedonia.

    PubMed

    Segarra, Nuria; Metastasio, Antonio; Ziauddeen, Hisham; Spencer, Jennifer; Reinders, Niels R; Dudas, Robert B; Arrondo, Gonzalo; Robbins, Trevor W; Clark, Luke; Fletcher, Paul C; Murray, Graham K

    2016-07-01

    Alterations in reward processes may underlie motivational and anhedonic symptoms in depression and schizophrenia. However it remains unclear whether these alterations are disorder-specific or shared, and whether they clearly relate to symptom generation or not. We studied brain responses to unexpected rewards during a simulated slot-machine game in 24 patients with depression, 21 patients with schizophrenia, and 21 healthy controls using functional magnetic resonance imaging. We investigated relationships between brain activation, task-related motivation, and questionnaire rated anhedonia. There was reduced activation in the orbitofrontal cortex, ventral striatum, inferior temporal gyrus, and occipital cortex in both depression and schizophrenia in comparison with healthy participants during receipt of unexpected reward. In the medial prefrontal cortex both patient groups showed reduced activation, with activation significantly more abnormal in schizophrenia than depression. Anterior cingulate and medial frontal cortical activation predicted task-related motivation, which in turn predicted anhedonia severity in schizophrenia. Our findings provide evidence for overlapping hypofunction in ventral striatal and orbitofrontal regions in depression and schizophrenia during unexpected reward receipt, and for a relationship between unexpected reward processing in the medial prefrontal cortex and the generation of motivational states.

  15. Regulatory RNAs discovered in unexpected places.

    PubMed

    Pek, Jun Wei; Okamura, Katsutomo

    2015-01-01

    Recent studies have discovered both small and long noncoding RNAs (ncRNAs) encoded in unexpected places. These ncRNA genes were surprises at the time of their discovery, but many quickly became well-accepted families of functional regulatory RNA species. Even after years of extensive gene annotation studies using high-throughput sequencing technologies, new types of ncRNA genes continue to be discovered in unexpected places. We highlight ncRNAs that have atypical structures and that are encoded in what are generally considered 'junk' sequences, such as spacers and introns. We also discuss current bottlenecks in the approaches for identifying novel ncRNAs and the possibility that many remain to be discovered. PMID:26424536

  16. BaBar: Searching for the Unexpected

    SciTech Connect

    Roodman, Aaron

    2006-04-24

    With over 300 million B-Bbar pairs delivered by the PEP-II B-factory, and over 200 publications, the Babar experiment has studied a very broad range of B, charm, tau, and QCD topics. In fact, the physics at Babar is so wide-ranging that it threatens to overwhelm any summary. Instead, in this colloquium I will focus on just a few topics selected for their potential to find a truly unexpected result. These include CP violation in rare B decays, leptonic B decays, and lepton-flavor violating tau decays. Each measurement, the currently predicted result, and the potential for uncovering the unexpected now and into the future, will be gently, but thoroughly, described.

  17. Language learning and brain reorganization in a 3.5-year-old child with left perinatal stroke revealed using structural and functional connectivity.

    PubMed

    François, Clément; Ripollés, Pablo; Bosch, Laura; Garcia-Alix, Alfredo; Muchart, Jordi; Sierpowska, Joanna; Fons, Carme; Solé, Jorgina; Rebollo, Monica; Gaitán, Helena; Rodriguez-Fornells, Antoni

    2016-04-01

    Brain imaging methods have contributed to shed light on the possible mechanisms of recovery and cortical reorganization after early brain insult. The idea that a functional left hemisphere is crucial for achieving a normalized pattern of language development after left perinatal stroke is still under debate. We report the case of a 3.5-year-old boy born at term with a perinatal ischemic stroke of the left middle cerebral artery, affecting mainly the supramarginal gyrus, superior parietal and insular cortex extending to the precentral and postcentral gyri. Neurocognitive development was assessed at 25 and 42 months of age. Language outcomes were more extensively evaluated at the latter age with measures on receptive vocabulary, phonological whole-word production and linguistic complexity in spontaneous speech. Word learning abilities were assessed using a fast-mapping task to assess immediate and delayed recall of newly mapped words. Functional and structural imaging data as well as a measure of intrinsic connectivity were also acquired. While cognitive, motor and language levels from the Bayley Scales fell within the average range at 25 months, language scores were below at 42 months. Receptive vocabulary fell within normal limits but whole word production was delayed and the child had limited spontaneous speech. Critically, the child showed clear difficulties in both the immediate and delayed recall of the novel words, significantly differing from an age-matched control group. Neuroimaging data revealed spared classical cortical language areas but an affected left dorsal white-matter pathway together with right lateralized functional activations. In the framework of the model for Social Communication and Language Development, these data confirm the important role of the left arcuate fasciculus in understanding and producing morpho-syntactic elements in sentences beyond two word combinations and, most importantly, in learning novel word-referent associations, a

  18. A Translational Murine Model of Sub-Lethal Intoxication with Shiga Toxin 2 Reveals Novel Ultrastructural Findings in the Brain Striatum

    PubMed Central

    Tironi-Farinati, Carla; Geoghegan, Patricia A.; Cangelosi, Adriana; Pinto, Alipio; Loidl, C. Fabian; Goldstein, Jorge

    2013-01-01

    Infection by Shiga toxin-producing Escherichia coli causes hemorrhagic colitis, hemolytic uremic syndrome (HUS), acute renal failure, and also central nervous system complications in around 30% of the children affected. Besides, neurological deficits are one of the most unrepairable and untreatable outcomes of HUS. Study of the striatum is relevant because basal ganglia are one of the brain areas most commonly affected in patients that have suffered from HUS and since the deleterious effects of a sub-lethal dose of Shiga toxin have never been studied in the striatum, the purpose of this study was to attempt to simulate an infection by Shiga toxin-producing E. coli in a murine model. To this end, intravenous administration of a sub-lethal dose of Shiga toxin 2 (0.5 ηg per mouse) was used and the correlation between neurological manifestations and ultrastructural changes in striatal brain cells was studied in detail. Neurological manifestations included significant motor behavior abnormalities in spontaneous motor activity, gait, pelvic elevation and hind limb activity eight days after administration of the toxin. Transmission electron microscopy revealed that the toxin caused early perivascular edema two days after administration, as well as significant damage in astrocytes four days after administration and significant damage in neurons and oligodendrocytes eight days after administration. Interrupted synapses and mast cell extravasation were also found eight days after administration of the toxin. We thus conclude that the chronological order of events observed in the striatum could explain the neurological disorders found eight days after administration of the toxin. PMID:23383285

  19. Metabolomic Analyses of Brain Tissue in Sepsis Induced by Cecal Ligation Reveal Specific Redox Alterations--Protective Effects of the Oxygen Radical Scavenger Edaravone.

    PubMed

    Hara, Naomi; Chijiiwa, Miyuki; Yara, Miki; Ishida, Yusuke; Ogiwara, Yukihiko; Inazu, Masato; Kuroda, Masahiko; Karlsson, Michael; Sjovall, Fredrik; Elmér, Eskil; Uchino, Hiroyuki

    2015-12-01

    The pathophysiology of sepsis-associated encephalopathy (SAE) is complex and remains incompletely elucidated. Dysregulated reactive oxygen species (ROS) production and mitochondrial-mediated necrotic-apoptotic pathway have been proposed as part of the pathogenesis. The present study aimed at analyzing the preventive effect of the free radical scavenger edaravone on sepsis-induced brain alterations. Sepsis was induced by cecal ligation and puncture (CLP) and the mice were divided into three groups-CLP vehicle (CLPV), CLP and edaravone (MCI-186, 3-methyl-1-phenyl-2-pyrazolin-5-one) (CLPE), and sham-operated (Sham). Mice in CLPV and CLPE were injected with saline or edaravone intraperitoneally at a dose of 10 mg/kg twice daily. The treatments were initiated 4 days prior to the surgical procedure. Mortality, histological changes, electron microscopy (EM), and expression of Bcl-2 family genes (Bcl-2 and Bax) were analyzed in selected brain regions. CLPE showed significant improvement in survival compared with CLPV 18 h postinduction of sepsis (P < 0.05). At the same time point, pathohistological analysis also showed marked reduction of neuronal cell death in both parietal cortex and hippocampus in the CLPE (P < 0.05). RT-PCR and immunoblotting directed at the Bcl-2 family revealed increased Bax mRNA levels in hippocampus at 12 h in CLPV as well as an increased Bax/Bcl-2 protein ratio, changes that were significantly suppressed in CLPE. In conclusion, our study suggests that sepsis induced by cecal ligation alters cerebral redox status and supports a proapoptotic phenotype. The free radical scavenger edavarone reduces mortality of septic mice and protects against sepsis-induced neuronal cell death.

  20. Manganese-enhanced magnetic resonance imaging (MEMRI) reveals brain circuitry involved in responding to an acute novel stress in rats with a history of repeated social stress

    PubMed Central

    Bangasser, Debra A.; Lee, Catherine S.; Cook, Philip A.; Gee, James C.; Bhatnagar, Seema; Valentino, Rita J.

    2013-01-01

    Responses to acute stressors are determined in part by stress history. For example, a history of chronic stress results in facilitated responses to a novel stressor and this facilitation is considered to be adaptive. We previously demonstrated that repeated exposure of rats to the resident-intruder model of social stress results in the emergence of two subpopulations that are characterized by different coping responses to stress. The submissive subpopulation failed to show facilitation to a novel stressor and developed a passive strategy in the Porsolt forced swim test. Because a passive stress coping response has been implicated in the propensity to develop certain psychiatric disorders, understanding the unique circuitry engaged by exposure to a novel stressor in these subpopulations would advance our understanding of the etiology of stress-related pathology. An ex vivo functional imaging technique, manganese-enhanced magnetic resonance imaging (MEMRI), was used to identify and distinguish brain regions that are differentially activated by an acute swim stress (15 min) in rats with a history of social stress compared to controls. Specifically, Mn2+ was administered intracerebroventricularly prior to swim stress and brains were later imaged ex vivo to reveal activated structures. When compared to controls, all rats with a history of social stress showed greater activation in specific striatal, hippocampal, hypothalamic, and midbrain regions. The submissive subpopulation of rats was further distinguished by significantly greater activation in amygdala, bed nucleus of the stria terminalis, and septum, suggesting that these regions may form a circuit mediating responses to novel stress in individuals that adopt passive coping strategies. The finding that different circuits are engaged by a novel stressor in the two subpopulations of rats exposed to social stress implicates a role for these circuits in determining individual strategies for responding to stressors

  1. Offsetting unexpected healthcare costs with futures contracts.

    PubMed

    Bond, M T; Marshall, B S

    1994-12-01

    Group health insurance futures contracts will be traded at the Chicago Board of Trade in the near future. These contracts may be useful devices for capitated systems, such as health maintenance organizations (HMOs), to hedge unanticipated increases in the costs of providing health care. This article discusses how futures contracts may be used by an HMO to prevent financial losses that arise from unexpected increases in inpatient utilization.

  2. Illustrations of Unexpected Infant Sleep Deaths.

    PubMed

    Cullen, Deborah; Oberle, Morgan; Elomba, Charles D; Stiffler, Deborah; Luna, Gaye

    2016-01-01

    Case illustrations from central Indiana provide the narrative for infant suffocations because of unsafe sleep environments. Accidental strangulation or suffocation in bed is caused by co-bedding, blankets and pillows in cribs, or wedging and entrapment. Knowledge of the evidence-based risks associated with case data may assist further in the prevention of unexpected infant sleep deaths and may better inform best practice for death scene investigation including forensic nurses. PMID:27496648

  3. Metabolomics analysis reveals elevation of 3-indoxyl sulfate in plasma and brain during chemically-induced acute kidney injury in mice: Investigation of nicotinic acid receptor agonists

    SciTech Connect

    Zgoda-Pols, Joanna R.; Chowdhury, Swapan; Wirth, Mark; Milburn, Michael V.; Alexander, Danny C.; Alton, Kevin B.

    2011-08-15

    An investigative renal toxicity study using metabolomics was conducted with a potent nicotinic acid receptor (NAR) agonist, SCH 900424. Liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) techniques were used to identify small molecule biomarkers of acute kidney injury (AKI) that could aid in a better mechanistic understanding of SCH 900424-induced AKI in mice. The metabolomics study revealed 3-indoxyl sulfate (3IS) as a more sensitive marker of SCH 900424-induced renal toxicity than creatinine or urea. An LC-MS assay for quantitative determination of 3IS in mouse matrices was also developed. Following treatment with SCH 900424, 3IS levels were markedly increased in murine plasma and brain, thereby potentially contributing to renal- and central nervous system (CNS)-related rapid onset of toxicities. Furthermore, significant decrease in urinary excretion of 3IS in those animals due to compromised renal function may be associated with the elevation of 3IS in plasma and brain. These data suggest that 3IS has a potential to be a marker of renal and CNS toxicities during chemically-induced AKI in mice. In addition, based on the metabolomic analysis other statistically significant plasma markers including p-cresol-sulfate and tryptophan catabolites (kynurenate, kynurenine, 3-indole-lactate) might be of toxicological importance but have not been studied in detail. This comprehensive approach that includes untargeted metabolomic and targeted bioanalytical sample analyses could be used to investigate toxicity of other compounds that pose preclinical or clinical development challenges in a pharmaceutical discovery and development. - Research Highlights: > Nicotinic acid receptor agonist, SCH 900424, caused acute kidney injury in mice. > MS-based metabolomics was conducted to identify potential small molecule markers of renal toxicity. > 3-indoxyl-sulfate was found to be as a more sensitive marker of renal toxicity than creatinine

  4. Stretched peer-review on unexpected results (GMOs).

    PubMed

    Myhr, A I

    2005-01-01

    Science is the basis for governance of risk from genetically modified organisms (GMO), and it is also a primary source of legitimacy for policy decision. However, recently the publication of unexpected results has caused controversies and challenged the way in which science should be performed, be published in scientific journals, and how preliminary results should be communicated. These studies have subsequently, after being accepted for publication within the peer-review process of leading scientific journals, been thoroughly re-examined by many actors active within the GMO debate and thereby drawn extensive media coverage. The publicized charges that the research involved does not constitute significant evidence or represent bad science have in fact deflected attention away from the important questions related to ecological and health risks raised by the research. In this paper, I will argue that unexpected findings may represent "early warnings." Although early warnings may not represent reality, such reports are necessary to inform other scientists and regulators, and should be followed up by further research to reveal the validity of the warnings. Furthermore, science that embraces robust, participatory and transparent approaches will be imperative in the future to reduce the present controversy surrounding GMO use and release.

  5. Analysis of Post-Traumatic Brain Injury Gene Expression Signature Reveals Tubulins, Nfe2l2, Nfkb, Cd44, and S100a4 as Treatment Targets.

    PubMed

    Lipponen, Anssi; Paananen, Jussi; Puhakka, Noora; Pitkänen, Asla

    2016-01-01

    We aimed to define the chronically altered gene expression signature of traumatic brain injury (TBI-sig) to discover novel treatments to reverse pathologic gene expression or reinforce the expression of recovery-related genes. Genome-wide RNA-sequencing was performed at 3 months post-TBI induced by lateral fluid-percussion injury in rats. We found 4964 regulated genes in the perilesional cortex and 1966 in the thalamus (FDR < 0.05). TBI-sig was used for a LINCS analysis which identified 11 compounds that showed a strong connectivity with the TBI-sig in neuronal cell lines. Of these, celecoxib and sirolimus were recently reported to have a disease-modifying effect in in vivo animal models of epilepsy. Other compounds revealed by the analysis were BRD-K91844626, BRD-A11009626, NO-ASA, BRD-K55260239, SDZ-NKT-343, STK-661558, BRD-K75971499, ionomycin, and desmethylclomipramine. Network analysis of overlapping genes revealed the effects on tubulins (Tubb2a, Tubb3, Tubb4b), Nfe2l2, S100a4, Cd44, and Nfkb2, all of which are linked to TBI-relevant outcomes, including epileptogenesis and tissue repair. Desmethylclomipramine modulated most of the gene targets considered favorable for TBI outcome. Our data demonstrate long-lasting transcriptomics changes after TBI. LINCS analysis predicted that these changes could be modulated by various compounds, some of which are already in clinical use but never tested in TBI. PMID:27530814

  6. Analysis of Post-Traumatic Brain Injury Gene Expression Signature Reveals Tubulins, Nfe2l2, Nfkb, Cd44, and S100a4 as Treatment Targets

    PubMed Central

    Lipponen, Anssi; Paananen, Jussi; Puhakka, Noora; Pitkänen, Asla

    2016-01-01

    We aimed to define the chronically altered gene expression signature of traumatic brain injury (TBI-sig) to discover novel treatments to reverse pathologic gene expression or reinforce the expression of recovery-related genes. Genome-wide RNA-sequencing was performed at 3 months post-TBI induced by lateral fluid-percussion injury in rats. We found 4964 regulated genes in the perilesional cortex and 1966 in the thalamus (FDR < 0.05). TBI-sig was used for a LINCS analysis which identified 11 compounds that showed a strong connectivity with the TBI-sig in neuronal cell lines. Of these, celecoxib and sirolimus were recently reported to have a disease-modifying effect in in vivo animal models of epilepsy. Other compounds revealed by the analysis were BRD-K91844626, BRD-A11009626, NO-ASA, BRD-K55260239, SDZ-NKT-343, STK-661558, BRD-K75971499, ionomycin, and desmethylclomipramine. Network analysis of overlapping genes revealed the effects on tubulins (Tubb2a, Tubb3, Tubb4b), Nfe2l2, S100a4, Cd44, and Nfkb2, all of which are linked to TBI-relevant outcomes, including epileptogenesis and tissue repair. Desmethylclomipramine modulated most of the gene targets considered favorable for TBI outcome. Our data demonstrate long-lasting transcriptomics changes after TBI. LINCS analysis predicted that these changes could be modulated by various compounds, some of which are already in clinical use but never tested in TBI. PMID:27530814

  7. Brain imaging reveals that engagement of descending inhibitory pain pathways in healthy women in a low endogenous estradiol state varies with testosterone.

    PubMed

    Vincent, Katy; Warnaby, Catherine; Stagg, Charlotte J; Moore, Jane; Kennedy, Stephen; Tracey, Irene

    2013-04-01

    The combined oral contraceptive pill (COCP) has been implicated in the development of a number of chronic pain conditions. Modern COCP formulations produce a low endogenous estradiol, low progesterone environment similar to the early follicular phase of the natural menstrual cycle, with a variable effect on serum androgen levels. We used behavioural measures and functional magnetic resonance imaging to investigate the response to experimental thermal stimuli in healthy women, in both a natural and COCP-induced low endogenous estradiol state, to investigate whether alterations in central pain processing may underlie these observations in COCP users. Although COCP users overall did not require lower temperatures to obtain a fixed pain intensity, alterations in the brain response to these stimuli were observed. In a subgroup of COCP users with significantly reduced serum testosterone, however, lower temperatures were required. Region-of-interest analysis revealed that within key regions of the descending pain inhibitory system, activity in response to noxious stimulation varied with serum testosterone levels in both groups of women. Of particular interest, in COCP users, activity in the rostral ventromedial medulla increased with increasing testosterone and in those women with low testosterone, was significantly reduced compared to controls. These findings suggest that, in a low endogenous estradiol state, testosterone may be a key factor in modulating pain sensitivity via descending pathways. Specifically, failure to engage descending inhibition at the level of the rostral ventromedial medulla may be responsible for the reduction in temperature required by COCP users with low circulating testosterone. PMID:23318125

  8. Distinct BOLD fMRI Responses of Capsaicin-Induced Thermal Sensation Reveal Pain-Related Brain Activation in Nonhuman Primates

    PubMed Central

    Asad, Abu Bakar Ali; Seah, Stephanie; Baumgartner, Richard; Feng, Dai; Jensen, Andres; Manigbas, Elaine; Henry, Brian; Houghton, Andrea; Evelhoch, Jeffrey L.; Derbyshire, Stuart W. G.; Chin, Chih-Liang

    2016-01-01

    Background Approximately 20% of the adult population suffer from chronic pain that is not adequately treated by current therapies, highlighting a great need for improved treatment options. To develop effective analgesics, experimental human and animal models of pain are critical. Topically/intra-dermally applied capsaicin induces hyperalgesia and allodynia to thermal and tactile stimuli that mimics chronic pain and is a useful translation from preclinical research to clinical investigation. Many behavioral and self-report studies of pain have exploited the use of the capsaicin pain model, but objective biomarker correlates of the capsaicin augmented nociceptive response in nonhuman primates remains to be explored. Methodology Here we establish an aversive capsaicin-induced fMRI model using non-noxious heat stimuli in Cynomolgus monkeys (n = 8). BOLD fMRI data were collected during thermal challenge (ON:20 s/42°C; OFF:40 s/35°C, 4-cycle) at baseline and 30 min post-capsaicin (0.1 mg, topical, forearm) application. Tail withdrawal behavioral studies were also conducted in the same animals using 42°C or 48°C water bath pre- and post- capsaicin application (0.1 mg, subcutaneous, tail). Principal Findings Group comparisons between pre- and post-capsaicin application revealed significant BOLD signal increases in brain regions associated with the ‘pain matrix’, including somatosensory, frontal, and cingulate cortices, as well as the cerebellum (paired t-test, p<0.02, n = 8), while no significant change was found after the vehicle application. The tail withdrawal behavioral study demonstrated a significant main effect of temperature and a trend towards capsaicin induced reduction of latency at both temperatures. Conclusions These findings provide insights into the specific brain regions involved with aversive, ‘pain-like’, responses in a nonhuman primate model. Future studies may employ both behavioral and fMRI measures as translational biomarkers to gain

  9. Unexpected cytological diagnosis of two cases of echinococcosis.

    PubMed

    Giuffré, G; Mondello, P; Inferrera, A; Furchì, A; Gentile, H M; Speciale, G

    1993-01-01

    The Authors report two cases of hydatid cysts localized in the soft tissues of the thigh and in para-renal region respectively. In both cases the cystic nature of the lesion was revealed by echography while the common serologic and hematologic preoperative tests did not show pathologic values. The working diagnosis was traumatic or developmental lesion and the patients were undergone to fine needle aspiration (FNA) cytology which permitted to make the unexpected diagnosis of hydatid cysts. The enzyme linked immunosorbent assay for echinococcus, done at the time in monitoring the disease, was positive only in one case. Although the routine use of FNA cytology for the diagnosis of echinococcosis should be discouraged, this procedure may represent a real aid in the definitive diagnose of clinically unsuspected hydatid cysts.

  10. The role of domain expertise and judgment in dealing with unexpected events

    NASA Astrophysics Data System (ADS)

    Kochan, Janeen Adrion

    Unexpected events, particularly those creating surprise, interrupt ongoing mental and behavioral processes, creating an increased potential for unwanted outcomes to the situation. Human reactions to unexpected events vary. One can hypothesize a number of reasons for this variation, including level of domain expertise, previous experience with similar events, emotional connotation, and the contextual surround of the event. Whereas interrupting ongoing activities and focusing attention temporarily on a surprising event may be a useful evolutionary response to a threatening situation, the same process may be maladaptive in today's highly dynamic world. The purpose of this study was to investigate how different aspects of expertise affected one's ability to detect and react to an unexpected event. It was hypothesized that there were two general types of expertise, domain expertise and judgment (Hammond, 2000), which influenced one's performance on dealing with an unexpected event. The goal of the research was to parse out the relative contribution of domain expertise, so the role of judgment could be revealed. The research questions for this study were: (a) Can we identify specific knowledges and skills which enhance one's ability to deal with unexpected events? (b) Are these skills "automatically" included in domain expertise? (c) How does domain expertise improve or deter one's reaction and response to unexpected events? (d) What role does judgment play in responding to surprise? The general hypothesis was that good judgment would influence the process of surprise at different stages and in different ways than would domain expertise. The conclusions from this research indicated that good judgment had a significant positive effect in helping pilots deal with unexpected events. This was most pronounced when domain expertise was low.

  11. Voxel-based morphometry and fMRI revealed differences in brain gray matter in breastfed and milk formula–fed children

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background and Purpose: Infant diets may have significant impact on brain development in children. The aim of this study was to evaluate brain grey matter structure and function in 8-year-old children who were predominantly breastfed (BF) or fed cow’s milk formula (MF) as infants. Materials and Me...

  12. Deep brain stimulation reveals a dissociation of consummatory and motivated behaviour in the medial and lateral nucleus accumbens shell of the rat.

    PubMed

    van der Plasse, Geoffrey; Schrama, Regina; van Seters, Sebastiaan P; Vanderschuren, Louk J M J; Westenberg, Herman G M

    2012-01-01

    Following the successful application of deep brain stimulation (DBS) in the treatment of Parkinson's disease and promising results in clinical trials for obsessive compulsive disorder and major depression, DBS is currently being tested in small patient-populations with eating disorders and addiction. However, in spite of its potential use in a broad spectrum of disorders, the mechanisms of action of DBS remain largely unclear and optimal neural targets for stimulation in several disorders have yet to be established. Thus, there is a great need to examine site-specific effects of DBS on a behavioural level and to understand how DBS may modulate pathological behaviour. In view of the possible application of DBS in the treatment of disorders characterized by impaired processing of reward and motivation, like addiction and eating disorders, we examined the effect of DBS of the nucleus accumbens (NAcc) on food-directed behavior. Rats were implanted with bilateral stimulation electrodes in one of three anatomically and functionally distinct sub-areas of the NAcc: the core, lateral shell (lShell) and medial shell (mShell). Subsequently, we studied the effects of DBS on food consumption, and the motivational and appetitive properties of food. The data revealed a functional dissociation between the lShell and mShell. DBS of the lShell reduced motivation to respond for sucrose under a progressive ratio schedule of reinforcement, mShell DBS, however, profoundly and selectively increased the intake of chow. DBS of the NAcc core did not alter any form of food-directed behavior studied. DBS of neither structure affected sucrose preference. These data indicate that the intake of chow and the motivation to work for palatable food can independently be modulated by DBS of subregions of the NAcc shell. As such, these findings provide important leads for the possible future application of DBS as a treatment for eating disorders such as anorexia nervosa. PMID:22428054

  13. Brain-based translation: fMRI decoding of spoken words in bilinguals reveals language-independent semantic representations in anterior temporal lobe.

    PubMed

    Correia, João; Formisano, Elia; Valente, Giancarlo; Hausfeld, Lars; Jansma, Bernadette; Bonte, Milene

    2014-01-01

    Bilinguals derive the same semantic concepts from equivalent, but acoustically different, words in their first and second languages. The neural mechanisms underlying the representation of language-independent concepts in the brain remain unclear. Here, we measured fMRI in human bilingual listeners and reveal that response patterns to individual spoken nouns in one language (e.g., "horse" in English) accurately predict the response patterns to equivalent nouns in the other language (e.g., "paard" in Dutch). Stimuli were four monosyllabic words in both languages, all from the category of "animal" nouns. For each word, pronunciations from three different speakers were included, allowing the investigation of speaker-independent representations of individual words. We used multivariate classifiers and a searchlight method to map the informative fMRI response patterns that enable decoding spoken words within languages (within-language discrimination) and across languages (across-language generalization). Response patterns discriminative of spoken words within language were distributed in multiple cortical regions, reflecting the complexity of the neural networks recruited during speech and language processing. Response patterns discriminative of spoken words across language were limited to localized clusters in the left anterior temporal lobe, the left angular gyrus and the posterior bank of the left postcentral gyrus, the right posterior superior temporal sulcus/superior temporal gyrus, the right medial anterior temporal lobe, the right anterior insula, and bilateral occipital cortex. These results corroborate the existence of "hub" regions organizing semantic-conceptual knowledge in abstract form at the fine-grained level of within semantic category discriminations.

  14. Unexpected Strong Decay Mode of Superheavy Nuclei

    NASA Astrophysics Data System (ADS)

    Poenaru, D. N.; Gherghescu, R. A.; Greiner, W.

    Calculations of half-lives of superheavy nuclei (SH) show an unexpected result: for some of them heavy particle radioactivity (HPR) dominates over alpha decay—the main decay mode of the majority of recently discovered SHs. The result is important for theory and future experiments producing heavier SHs with a substantial amount of funding. The standard identification technique by alpha decay chains will be impossible for these cases. HPR had been predicted in 1980 four years before the first experiment. The daughter is mainly the doubly magic ^{208}Pb. We changed the concept of HPR to allow emitted particles with Z_e > 28from parents with Z > 110 (daughter around ^{208}Pb). We find a trend toward shorter half-lives and larger branching ratios relative to alpha decay for heavier SHs. A new table of measured masses AME11 and the theoretical LiMaZe01, KTUY05 and FRDM95 tables are used to determine Q-values.

  15. Unexpected consequences of midwifery in the NHS.

    PubMed

    Pollock, Jane

    2015-11-01

    This article presents information from the Caring for the carers conference held at George Eliot Hospital in July 2015. For many midwives, feelings of stress are an unexpected consequence of rising birth rates, low staffing levels and negative organisational cultures, so our aim was that delegates would take away skills for 'surviving' in maternity services. The conference was the catalyst to a project at George Eliot NHS Trust to improve the wellbeing of staff so that they can develop a positive outlook towards the care which they offer. As part of the project, a toolkit for survival was produced which helps to prompt maternity workers to remember their own wellbeing. This project is continuing to grow and the results will be available next year. PMID:26669051

  16. Nasal foreign body: an unexpected discovery.

    PubMed

    Yasny, Jeffrey S; Stewart, Stacy

    2011-01-01

    Abstract Nasal foreign bodies may result from the abundant availability of tiny objects in our society and a curious child exploring his or her nasal cavities. An inserted object that is not witnessed or retrieved can remain relatively asymptomatic or cause local tissue damage and potentially yield more serious consequences. An unusual case of a young child who presented for dental rehabilitation under general anesthesia is described. Immediately prior to the nasotracheal intubation, an unanticipated foreign body was detected and safely removed before any injury occurred. This case report discusses the presentation and pathophysiology of nasal foreign bodies. Moreover, applicable suggestions are provided to aid in the prevention and management of the unexpected discovery of a nasal foreign body after the induction of general anesthesia.

  17. Unexpected features of the dark proteome

    PubMed Central

    Perdigão, Nelson; Heinrich, Julian; Stolte, Christian; Sabir, Kenneth S.; Buckley, Michael J.; Tabor, Bruce; Signal, Beth; Gloss, Brian S.; Hammang, Christopher J.; Rost, Burkhard; Schafferhans, Andrea

    2015-01-01

    We surveyed the “dark” proteome–that is, regions of proteins never observed by experimental structure determination and inaccessible to homology modeling. For 546,000 Swiss-Prot proteins, we found that 44–54% of the proteome in eukaryotes and viruses was dark, compared with only ∼14% in archaea and bacteria. Surprisingly, most of the dark proteome could not be accounted for by conventional explanations, such as intrinsic disorder or transmembrane regions. Nearly half of the dark proteome comprised dark proteins, in which the entire sequence lacked similarity to any known structure. Dark proteins fulfill a wide variety of functions, but a subset showed distinct and largely unexpected features, such as association with secretion, specific tissues, the endoplasmic reticulum, disulfide bonding, and proteolytic cleavage. Dark proteins also had short sequence length, low evolutionary reuse, and few known interactions with other proteins. These results suggest new research directions in structural and computational biology. PMID:26578815

  18. Assigning cause for sudden unexpected infant death.

    PubMed

    Hunt, Carl E; Darnall, Robert A; McEntire, Betty L; Hyma, Bruce A

    2015-06-01

    We have reached a conundrum in assigning cause of death for sudden unexpected infant deaths. We summarize the discordant perspectives and approaches and how they have occurred, and recommend a pathway toward improved consistency. This lack of consistency affects pediatricians and other health care professionals, scientific investigators, medical examiners and coroners, law enforcement agencies, families, and support or advocacy groups. We recommend that an interdisciplinary international committee be organized to review current approaches for assigning cause of death, and to identify a consensus strategy for improving consistency. This effort will need to encompass intrinsic risk factors or infant vulnerability in addition to known environmental risk factors including unsafe sleep settings, and must be sufficiently flexible to accommodate a progressively expanding knowledge base. PMID:25634430

  19. Unexpected consequences of midwifery in the NHS.

    PubMed

    Pollock, Jane

    2015-11-01

    This article presents information from the Caring for the carers conference held at George Eliot Hospital in July 2015. For many midwives, feelings of stress are an unexpected consequence of rising birth rates, low staffing levels and negative organisational cultures, so our aim was that delegates would take away skills for 'surviving' in maternity services. The conference was the catalyst to a project at George Eliot NHS Trust to improve the wellbeing of staff so that they can develop a positive outlook towards the care which they offer. As part of the project, a toolkit for survival was produced which helps to prompt maternity workers to remember their own wellbeing. This project is continuing to grow and the results will be available next year.

  20. Unexpected features of the dark proteome.

    PubMed

    Perdigão, Nelson; Heinrich, Julian; Stolte, Christian; Sabir, Kenneth S; Buckley, Michael J; Tabor, Bruce; Signal, Beth; Gloss, Brian S; Hammang, Christopher J; Rost, Burkhard; Schafferhans, Andrea; O'Donoghue, Seán I

    2015-12-29

    We surveyed the "dark" proteome-that is, regions of proteins never observed by experimental structure determination and inaccessible to homology modeling. For 546,000 Swiss-Prot proteins, we found that 44-54% of the proteome in eukaryotes and viruses was dark, compared with only ∼14% in archaea and bacteria. Surprisingly, most of the dark proteome could not be accounted for by conventional explanations, such as intrinsic disorder or transmembrane regions. Nearly half of the dark proteome comprised dark proteins, in which the entire sequence lacked similarity to any known structure. Dark proteins fulfill a wide variety of functions, but a subset showed distinct and largely unexpected features, such as association with secretion, specific tissues, the endoplasmic reticulum, disulfide bonding, and proteolytic cleavage. Dark proteins also had short sequence length, low evolutionary reuse, and few known interactions with other proteins. These results suggest new research directions in structural and computational biology. PMID:26578815

  1. Cardiac ganglionitis associated with sudden unexpected death.

    PubMed

    James, T N; Zipes, D P; Finegan, R E; Eisele, J W; Carter, J E

    1979-11-01

    In a postmortem study of the hearts of two young women who died suddenly and unexpectedly, we found a remarkably similar and distinctive ganglionitis, predominantly in the region of the sinus node. Both women had ventricular fibrillation at the time of collapse. Vesicular neuritis and older neural degeneration were present in other regions of the heart. Except for focal fibromuscular dysplasia of the sinus node artery and atrioventricular node artery of one heart, there was no other significant anatomic abnormality in either heart. The functional significance of this cardiac ganglionitis is unclear, but its location in and around the conduction system makes it a possible cause of the fatal electrical instability. Recognition that ganglionitis of the heart may be associated with sudden death should stimulate a number of additionally useful studies.

  2. Unexpected features of the dark proteome.

    PubMed

    Perdigão, Nelson; Heinrich, Julian; Stolte, Christian; Sabir, Kenneth S; Buckley, Michael J; Tabor, Bruce; Signal, Beth; Gloss, Brian S; Hammang, Christopher J; Rost, Burkhard; Schafferhans, Andrea; O'Donoghue, Seán I

    2015-12-29

    We surveyed the "dark" proteome-that is, regions of proteins never observed by experimental structure determination and inaccessible to homology modeling. For 546,000 Swiss-Prot proteins, we found that 44-54% of the proteome in eukaryotes and viruses was dark, compared with only ∼14% in archaea and bacteria. Surprisingly, most of the dark proteome could not be accounted for by conventional explanations, such as intrinsic disorder or transmembrane regions. Nearly half of the dark proteome comprised dark proteins, in which the entire sequence lacked similarity to any known structure. Dark proteins fulfill a wide variety of functions, but a subset showed distinct and largely unexpected features, such as association with secretion, specific tissues, the endoplasmic reticulum, disulfide bonding, and proteolytic cleavage. Dark proteins also had short sequence length, low evolutionary reuse, and few known interactions with other proteins. These results suggest new research directions in structural and computational biology.

  3. Commentary: Unexpected Benefits that Challenge the Orthodoxy of DBS Outcomes.

    PubMed

    Ford, Paul

    2016-10-01

    The case of Ms. L. provides a wonderful opportunity to highlight the underlying value commitments that often deeply influence decisionmaking in medicine and more specifically in innovative neurosurgical procedures. In order to give a fair opinion on how Dr. Impf, as clinician and researcher, should act, a much richer and thicker understanding of the actual perspectives of the stakeholders would be necessary. Because this is not available, I highlight three important elements: the terms under which the deep brain stimulation (DBS) is implanted, the proper goals of a healthcare team, and the fallacy of a "natural" or immutable self. These elements are brought together in this case by a set of unexpected effects on the patient that were not intended and that are judged and categorized differently by various stakeholders within the case. In the end, I hope that there was full transparency and agreement about obligations, responsibilities, and outcomes prior to the implantation of the DBS between the physician and patient. Further, it is important to remember that just because a result is serendipitous does not mean that it should be discounted as a proper benefit. Finally, each person authors variations on their own self that are molded by environment and social networks. If Ms. L. continues to demonstrate an ability to author a desired self, the DBS is no more inappropriate a tool than many other artifacts that are used regularly by others to mold themselves. PMID:27634727

  4. Commentary: Unexpected Benefits that Challenge the Orthodoxy of DBS Outcomes.

    PubMed

    Ford, Paul

    2016-10-01

    The case of Ms. L. provides a wonderful opportunity to highlight the underlying value commitments that often deeply influence decisionmaking in medicine and more specifically in innovative neurosurgical procedures. In order to give a fair opinion on how Dr. Impf, as clinician and researcher, should act, a much richer and thicker understanding of the actual perspectives of the stakeholders would be necessary. Because this is not available, I highlight three important elements: the terms under which the deep brain stimulation (DBS) is implanted, the proper goals of a healthcare team, and the fallacy of a "natural" or immutable self. These elements are brought together in this case by a set of unexpected effects on the patient that were not intended and that are judged and categorized differently by various stakeholders within the case. In the end, I hope that there was full transparency and agreement about obligations, responsibilities, and outcomes prior to the implantation of the DBS between the physician and patient. Further, it is important to remember that just because a result is serendipitous does not mean that it should be discounted as a proper benefit. Finally, each person authors variations on their own self that are molded by environment and social networks. If Ms. L. continues to demonstrate an ability to author a desired self, the DBS is no more inappropriate a tool than many other artifacts that are used regularly by others to mold themselves.

  5. Knock-out models reveal new aquaporin functions.

    PubMed

    Verkman, Alan S

    2009-01-01

    Knockout mice have been informative in the discovery of unexpected biological functions of aquaporins. Knockout mice have confirmed the predicted roles of aquaporins in transepithelial fluid transport, as in the urinary concentrating mechanism and glandular fluid secretion. A less obvious, though predictable role of aquaporins is in tissue swelling under stress, as in the brain in stroke, tumor and infection. Phenotype analysis of aquaporin knockout mice has revealed several unexpected cellular roles of aquaporins whose mechanisms are being elucidated. Aquaporins facilitate cell migration, as seen in aquaporin-dependent tumor angiogenesis and tumor metastasis, by a mechanism that may involve facilitated water transport in lamellipodia of migrating cells. The ' aquaglyceroporins', aquaporins that transport both glycerol and water, regulate glycerol content in epidermis, fat and other tissues, and lead to a multiplicity of interesting consequences of gene disruption including dry skin, resistance to skin carcinogenesis, impaired cell proliferation and altered fat metabolism. An even more surprising role of a mammalian aquaporin is in neural signal transduction in the central nervous system. The many roles of aquaporins might be exploited for clinical benefit by modulation of aquaporin expression/function - as diuretics, and in the treatment of brain swelling, glaucoma, epilepsy, obesity and cancer. PMID:19096787

  6. Analyses of Resected Human Brain Metastases of Breast Cancer Reveal the Association between Up-regulation of Hexokinase 2 and Poor Prognosis

    PubMed Central

    Palmieri, Diane; Fitzgerald, Daniel; Shreeve, S. Martin; Hua, Emily; Bronder, Julie L.; Weil, Robert J.; Davis, Sean; Stark, Andreas M.; Merino, Maria J.; Kurek, Raffael; Mehdorn, H. Maximilian; Davis, Gary; Steinberg, Seth M.; Meltzer, Paul S.; Aldape, Kenneth; Steeg, Patricia S.

    2009-01-01

    Brain metastases of breast cancer appear to be increasing in incidence as systemic therapy improves. Metastatic disease in the brain is associated with high morbidity and mortality. We present the first gene expression analysis of laser captured epithelial cells from resected human brain metastases of breast cancer compared to unlinked primary breast tumors. The tumors were matched for histology, TNM stage and hormone receptor status. Most differentially expressed genes were down-regulated in the brain metastases which included, surprisingly, many genes associated with metastasis. Q-PCR analysis confirmed statistically significant differences or strong trends in the expression of six genes: BMP1, PEDF, LAMγ3, SIAH, STHMN3 and TSPD2. Hexokinase 2 (HK2) was also of interest because of its increased expression in brain metastases. HK2 is important in glucose metabolism and apoptosis. In agreement with our microarray results, HK2 levels (both mRNA and protein) were elevated in a brain metastatic derivative (231-BR) of the human breast carcinoma cell line MDA-MB-231 relative to the parental cell line (231-P), in vitro. Knockdown of HK2 expression in 231-BR cells using shRNA reduced cell proliferation when cultures were maintained in glucose limiting conditions. Finally, HK2 expression was analyzed in a cohort of 123 resected brain metastases of breast cancer. High HK2 expression was significantly associated with poor patient survival post-craniotomy (P=0.028). The data suggest that HK2 overexpression is associated with metastasis to the brain in breast cancer and it may be a therapeutic target. PMID:19723875

  7. Analyses of resected human brain metastases of breast cancer reveal the association between up-regulation of hexokinase 2 and poor prognosis.

    PubMed

    Palmieri, Diane; Fitzgerald, Daniel; Shreeve, S Martin; Hua, Emily; Bronder, Julie L; Weil, Robert J; Davis, Sean; Stark, Andreas M; Merino, Maria J; Kurek, Raffael; Mehdorn, H Maximilian; Davis, Gary; Steinberg, Seth M; Meltzer, Paul S; Aldape, Kenneth; Steeg, Patricia S

    2009-09-01

    Brain metastases of breast cancer seem to be increasingin incidence as systemic therapy improves. Metastatic disease in the brain is associated with high morbidity and mortality. We present the first gene expression analysis of laser-captured epithelial cells from resected human brain metastases of breast cancer compared with unlinked primary breast tumors. The tumors were matched for histology, tumor-node-metastasis stage, and hormone receptor status. Most differentially expressed genes were down-regulated in the brain metastases, which included, surprisingly, many genes associated with metastasis. Quantitative real-time PCR analysis confirmed statistically significant differences or strong trends in the expression of six genes: BMP1, PEDF, LAMgamma3, SIAH, STHMN3, and TSPD2. Hexokinase 2 (HK2) was also of interest because of its increased expression in brain metastases. HK2 is important in glucose metabolism and apoptosis. In agreement with our microarray results, HK2 levels (both mRNA and protein) were elevated in a brain metastatic derivative (231-BR) of the human breast carcinoma cell line MDA-MB-231 relative to the parental cell line (231-P) in vitro. Knockdown of HK2 expression in 231-BR cells using short hairpin RNA reduced cell proliferation when cultures were maintained in glucose-limiting conditions. Finally, HK2 expression was analyzed in a cohort of 123 resected brain metastases of breast cancer. High HK2 expression was significantly associated with poor patient survival after craniotomy (P = 0.028). The data suggest that HK2 overexpression is associated with metastasis to the brain in breast cancer and it may be a therapeutic target. PMID:19723875

  8. Sudden unexpected death in epilepsy: Evaluation of forensic autopsy cases.

    PubMed

    Zhuo, Luo; Zhang, Yang; Zielke, H Ronald; Levine, Barry; Zhang, Xiang; Chang, Lin; Fowler, David; Li, Ling

    2012-11-30

    Epilepsy is a common chronic neurological disorder characterized by seizures. Mortality is significantly increased in patients with epilepsy. Sudden unexpected death in epilepsy (SUDEP) is the most common seizure-related category of death. A retrospective study of forensic autopsy cases from 2007 to 2009 at the Office of the Chief Medical Examiner (OCME) yielded a total of 104 sudden unexpected deaths directly or indirectly caused by an epilepsy/seizure disorder in the State of Maryland. Of these deaths, 74 cases met a general accepted definition of SUDEP. The age of SUDEP individuals ranged from 14 to 63 with the majority of subjects in the ages between 21 and 50 years (58 cases, 78.4%). Males were slightly more likely than females to die of SUDEP (male:female=1.5:1 based on the rate). The onset age of epilepsy was documented in 47.3% of cases (35/74) based on investigation and medical records. Of the 35 cases, 12 subjects had early onset epilepsy (onset ages 1-15 years) and 20 subjects had duration of epilepsy for more than 10 years. The majority of deaths (61 of the 74 cases, 82.4%) were unwitnessed. Death scene investigation showed that 71 deaths (95.9%) occurred inside their residence with 50 subjects (70.4%) found either in bed or on the bedroom floor near the bed. Forty-three out of 74 cases (58.1%) showed neuropathological lesions. Per history, 50 subjects were reported as being on anti-epileptic drugs (AEDs). However, postmortem toxicological analysis revealed that only 26 subjects (35.1%) had detectable AEDs. Of the 74 cases, seizure disorder or epilepsy was listed as primary cause of death in 66 cases and the term of SUDEP as official cause of death in only 8 cases. This report focuses on the characteristics of death scene investigation and postmortem examination findings of SUDEP cases.

  9. The complement system: an unexpected role in synaptic pruning during development and disease.

    PubMed

    Stephan, Alexander H; Barres, Ben A; Stevens, Beth

    2012-01-01

    An unexpected role for the classical complement cascade in the elimination of central nervous system (CNS) synapses has recently been discovered. Complement proteins are localized to developing CNS synapses during periods of active synapse elimination and are required for normal brain wiring. The function of complement proteins in the brain appears analogous to their function in the immune system: clearance of cellular material that has been tagged for elimination. Similarly, synapses tagged with complement proteins may be eliminated by microglial cells expressing complement receptors. In addition, developing astrocytes release signals that induce the expression of complement components in the CNS. In the mature brain, early synapse loss is a hallmark of several neurodegenerative diseases. Complement proteins are profoundly upregulated in many CNS diseases prior to signs of neuron loss, suggesting a reactivation of similar developmental mechanisms of complement-mediated synapse elimination potentially driving disease progression.

  10. Fetal Alcohol Syndrome in Sudden Unexpected Death in Infancy: A Case Report in Medicolegal Autopsy.

    PubMed

    Tangsermkijsakul, Aphinan

    2016-03-01

    Fetal alcohol spectrum disorder is a range of birth defects associated with prenatal alcohol exposure. Fetal alcohol syndrome (FAS) is the most serious form of fetal alcohol spectrum disorder. Infants with FAS are prone to death because of various physical abnormalities. Consequently, infants with FAS may be presented in the medicolegal investigation as a form of sudden unexpected death in infancy. The author reported a 6-month-old male infant who was found dead at home. The history of maternal ethanol consumption during pregnancy was obtained. The infant was diagnosed with FAS at the autopsy because he was presented with postnatal growth retardation, multiple facial abnormalities, and abnormal brain structures, which met the criteria of FAS. The cause of death was severe aspiration pneumonia. The purposes of this case report are to show an uncommon manifestation of sudden unexpected death in infancy case for the forensic pathologists and to emphasize on the national healthcare problem.

  11. Fetal Alcohol Syndrome in Sudden Unexpected Death in Infancy: A Case Report in Medicolegal Autopsy.

    PubMed

    Tangsermkijsakul, Aphinan

    2016-03-01

    Fetal alcohol spectrum disorder is a range of birth defects associated with prenatal alcohol exposure. Fetal alcohol syndrome (FAS) is the most serious form of fetal alcohol spectrum disorder. Infants with FAS are prone to death because of various physical abnormalities. Consequently, infants with FAS may be presented in the medicolegal investigation as a form of sudden unexpected death in infancy. The author reported a 6-month-old male infant who was found dead at home. The history of maternal ethanol consumption during pregnancy was obtained. The infant was diagnosed with FAS at the autopsy because he was presented with postnatal growth retardation, multiple facial abnormalities, and abnormal brain structures, which met the criteria of FAS. The cause of death was severe aspiration pneumonia. The purposes of this case report are to show an uncommon manifestation of sudden unexpected death in infancy case for the forensic pathologists and to emphasize on the national healthcare problem. PMID:26730801

  12. Comprehensive Identification of Long Non-coding RNAs in Purified Cell Types from the Brain Reveals Functional LncRNA in OPC Fate Determination

    PubMed Central

    Dong, Xiaomin; Chen, Kenian; Cuevas-Diaz Duran, Raquel; You, Yanan; Sloan, Steven A.; Zhang, Ye; Zong, Shan; Cao, Qilin; Barres, Ben A.; Wu, Jia Qian

    2015-01-01

    Long non-coding RNAs (lncRNAs) (> 200 bp) play crucial roles in transcriptional regulation during numerous biological processes. However, it is challenging to comprehensively identify lncRNAs, because they are often expressed at low levels and with more cell-type specificity than are protein-coding genes. In the present study, we performed ab initio transcriptome reconstruction using eight purified cell populations from mouse cortex and detected more than 5000 lncRNAs. Predicting the functions of lncRNAs using cell-type specific data revealed their potential functional roles in Central Nervous System (CNS) development. We performed motif searches in ENCODE DNase I digital footprint data and Mouse ENCODE promoters to infer transcription factor (TF) occupancy. By integrating TF binding and cell-type specific transcriptomic data, we constructed a novel framework that is useful for systematically identifying lncRNAs that are potentially essential for brain cell fate determination. Based on this integrative analysis, we identified lncRNAs that are regulated during Oligodendrocyte Precursor Cell (OPC) differentiation from Neural Stem Cells (NSCs) and that are likely to be involved in oligodendrogenesis. The top candidate, lnc-OPC, shows highly specific expression in OPCs and remarkable sequence conservation among placental mammals. Interestingly, lnc-OPC is significantly up-regulated in glial progenitors from experimental autoimmune encephalomyelitis (EAE) mouse models compared to wild-type mice. OLIG2-binding sites in the upstream regulatory region of lnc-OPC were identified by ChIP (chromatin immunoprecipitation)-Sequencing and validated by luciferase assays. Loss-of-function experiments confirmed that lnc-OPC plays a functional role in OPC genesis. Overall, our results substantiated the role of lncRNA in OPC fate determination and provided an unprecedented data source for future functional investigations in CNS cell types. We present our datasets and analysis results

  13. Sudden unexpected death due to severe pulmonary and cardiac sarcoidosis.

    PubMed

    Ginelliová, Alžbeta; Farkaš, Daniel; Farkašová Iannaccone, Silvia; Vyhnálková, Vlasta

    2016-09-01

    In this paper we report the autopsy findings of a 57 year old woman who died unexpectedly at home. She had been complaining of shortness of breath, episodes of dry coughing, and nausea. Her past medical and social history was unremarkable. She had no previous history of any viral or bacterial disease and no history of oncological disorders. Autopsy revealed multiple grayish-white nodular lesions in the pleura and epicardial fat and areas resembling fibrosis on the cut surface of the anterior and posterior wall of the left ventricle and interventricular septum. Histological examination of the lungs and heart revealed multiple well-formed noncaseating epithelioid cell granulomas with multinucleated giant cells. Death was attributed to myocardial ischemia due to vasculitis of intramural coronary artery branches associated with sarcoidosis. Sarcoidosis is a multisystemic disease of unknown etiology characterized by the formation of noncaseating epithelioid cell granulomas in the affected organs and tissues. The diagnosis of sarcoidosis in this case was established when other causes of granulomatous disease such as tuberculosis, berylliosis, hypersensitivity pneumonitis, and giant cell myocarditis had been reasonably excluded. PMID:27379608

  14. Sudden, unexpected death of a 15-year-old boy due to pancarditis

    PubMed Central

    Osculati, Antonio; Visonà, Silvia Damiana; Ventura, Francesco; Castelli, Francesca; Andrello, Luisa

    2016-01-01

    Abstract Background: Generally, rheumatic heart disease is, today, sporadic in developed countries, even though it continues to be a major health hazard in the developing ones. It is also a very rare cause of sudden unexpected death. We report a case of a 15-year-old boy who suddenly died at home. Since 3 days he had presented fever and chest pain. The family physician had diagnosed bronchitis and treated the boy with amoxicillin. Methods: Seven hours after death, a forensic autopsy were performed . Before the autopsy, anamnesis and some circumstantial data were collected from the boy's parents. During the autopsy, samples for histological, toxicological and molecular examinations were collected. The samples for the histology (brain, hypophysis, heart and pericardium, lungs, spleen, liver, kidney, adrenal glands) were formalin fixed and paraffin embedded. Each section was stained with Hematoxylin-Eosin. Immunostaining was also performed, with anti-CD 68, anti-CD3, anti-CD 20, anti-myeloperoxidase. Microbiological cultures were performed on cardiac blood, myocardium, pericardial effusion and cerebrospinal fluid samples collected during autopsy. Blood specimens were also processed through PCR, in order to reveal the presence of Enteroviruses, Chickenpox virus, Epstein Barr virus. Also chemical-toxicological examinations for the detection of the main medications and drugs were performed on blood samples. Results: The anamnesis, collected before the autopsy, revealed an acute pharyngitis few weeks before. The autopsy, and the following histological and immunochemical examinations suggested an immunological etiology. The immunohistochemistry, showing a strong positivity of antiCD68 antibodies, integrated with clinical-anamnestic information, leads to hypothesize a rheumatic carditis. Conclusion: In light of this case, at least 3 main messages of great importance for the clinician can be deduced. First, an accurate anamnesis collected by the family physician could have

  15. What happens to your brain on the way to Mars

    PubMed Central

    Parihar, Vipan K.; Allen, Barrett; Tran, Katherine K.; Macaraeg, Trisha G.; Chu, Esther M.; Kwok, Stephanie F.; Chmielewski, Nicole N.; Craver, Brianna M.; Baulch, Janet E.; Acharya, Munjal M.; Cucinotta, Francis A.; Limoli, Charles L.

    2015-01-01

    As NASA prepares for the first manned spaceflight to Mars, questions have surfaced concerning the potential for increased risks associated with exposure to the spectrum of highly energetic nuclei that comprise galactic cosmic rays. Animal models have revealed an unexpected sensitivity of mature neurons in the brain to charged particles found in space. Astronaut autonomy during long-term space travel is particularly critical as is the need to properly manage planned and unanticipated events, activities that could be compromised by accumulating particle traversals through the brain. Using mice subjected to space-relevant fluences of charged particles, we show significant cortical- and hippocampal-based performance decrements 6 weeks after acute exposure. Animals manifesting cognitive decrements exhibited marked and persistent radiation-induced reductions in dendritic complexity and spine density along medial prefrontal cortical neurons known to mediate neurotransmission specifically interrogated by our behavioral tasks. Significant increases in postsynaptic density protein 95 (PSD-95) revealed major radiation-induced alterations in synaptic integrity. Impaired behavioral performance of individual animals correlated significantly with reduced spine density and trended with increased synaptic puncta, thereby providing quantitative measures of risk for developing cognitive decrements. Our data indicate an unexpected and unique susceptibility of the central nervous system to space radiation exposure, and argue that the underlying radiation sensitivity of delicate neuronal structure may well predispose astronauts to unintended mission-critical performance decrements and/or longer-term neurocognitive sequelae. PMID:26180843

  16. Unexpected skin barrier influence from nonionic emulsifiers.

    PubMed

    Bárány, E; Lindberg, M; Lodén, M

    2000-02-15

    Skin disorders are often treated with creams containing various active substances. The creams also contain emulsifiers, which are surface-active ingredients used to stabilize the emulsion. Emulsifiers are potential irritants and in the present study the influence of stearic acid, glyceryl stearate, PEG-2, -9, -40, and -100 stearate, steareth-2, -10 and -21 on normal as well as on irritated skin have been evaluated with non-invasive measurements. Test emulsions were created by incorporating 5% emulsifiers in a water/mineral oil mixture (50:50). The emulsions and their vehicle were then applied to normal skin for 48 h and to sodium lauryl sulfate (SLS) damaged skin for 17 h in aluminum chambers. Twenty-four hours after removal of the chambers the test sites were evaluated for degree of irritation. In normal skin, the emulsifiers induced significant differences in TEWL but not in skin blood flow. Five of the emulsifiers increased TEWL. In SLS-damaged skin an aggravation of the irritation was expected. However, no differences regarding skin blood flow was noted from the emulsifiers. Furthermore, three emulsifiers unexpectedly decreased TEWL. These results highlight the possibility of absorption of these emulsifiers into the lipid bilayer, which increase TEWL in normal skin and decrease TEWL in damaged skin.

  17. Categories of preventable unexpected infant deaths.

    PubMed Central

    Taylor, E M; Emery, J L

    1990-01-01

    The conclusions of confidential inquiries into 115 registered unexpected infant deaths over a period of nine years were reviewed. Deaths were classified based on the total information available into group A: poor prognosis (n = 7), group B: treatable disease (n = 45), group C: minor disease (n = 32), group D: no disease (n = 19), group E: probably accidental (n = 4), and group F: probably filicide (n = 8). Less than 20% of deaths corresponded to the classic definition of sudden infant death syndrome (SIDS). Babies who died during the course of potentially treatable disease had more adverse family and social factors: the parents were less likely to be owner occupiers, or own a car or telephone, their mothers were more likely to be young, to smoke, and to present late in pregnancy. Babies who died of minor disease tended to come from similar backgrounds, their families had greater levels of stress and the deaths appeared to be due to more than one factor. Babies who died with no terminal disease were younger, and more likely to be boys. Their families appeared to be demographically similar to those of a control group and to the general population. PMID:2357095

  18. Unexpected responses to EGFR inhibition in NSCLC

    PubMed Central

    Stella, Giulia M.; Valizia, Claudio; Zorzetto, Michele; Inghilleri, Simona; Valentini, Adele; Dore, Roberto; Colombo, Sara; Valentino, Francesco; Orlandoni, Giulio; Morbini, Patrizia

    2015-01-01

    The presence of activating mutations of the epidermal growth factor receptor (EGFR)-gene identifies a distinct and clinically relevant molecular subset of non-small-cell lung cancer. It is now well demonstrated that EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib are superior to standard chemotherapy in this subset of tumors. Nevertheless, in many cases, responses are not durable and last for 6–12 months due to the occurrence of secondary or acquired resistance. Here we present three cases of EGFR-mutant lung adenocarcinomas (ADC), that showed an unexpected response to anti-EGFR small molecules. The first patient presented a continued 89 month-long response to erlotinib in a tumor recurred after surgery and conventional chemotherapy. In the other cases, subclinically persistent tumor in the lung tissue was documented histologically in lung resections performed after partial response to TKI treatment. The persistence of interstitial and endolymphatic tumor cells after TKI treatment might explain the common observation of tumor relapse after TKI discontinuation, and sustain the decision to continue treatment in responsive patients as in our first case. PMID:26744648

  19. Vicarious reinforcement: Expected and unexpected effects.

    PubMed

    Ollendick, T H; Dailey, D; Shapiro, E S

    1983-01-01

    The primary purpose of this study was to examine the effects on one child of observing another child receive direct social reinforcement. In the first part of the study, pairs of same-sex children worked on puzzles for three sessions spaced 2 to 3 days apart. One child was praised on a continuous schedule for performance, whereas the other received no praise. Although children who observed other children being praised increased their performance initially (as predicted by vicarious reinforcement and social comparison hypotheses), their performance decreased over time, reaching levels below their own baseline rates. In the second part of the study, intermittent praise delivered to the observing child was examined as a potential strategy to reverse the unexpected effects obtained in the first part of the study. Intermittent praise was found to be effective in reducing these effects and in producing enhanced performance. Individual data, as well as group data, are presented. Results are discussed in light of theoretical and applied issues related to the use of vicarious reinforcement in applied settings. PMID:16795669

  20. Diffusion tensor imaging reveals adolescent binge ethanol-induced brain structural integrity alterations in adult rats that correlate with behavioral dysfunction.

    PubMed

    Vetreno, Ryan P; Yaxley, Richard; Paniagua, Beatriz; Crews, Fulton T

    2016-07-01

    Adolescence is characterized by considerable brain maturation that coincides with the development of adult behavior. Binge drinking is common during adolescence and can have deleterious effects on brain maturation because of the heightened neuroplasticity of the adolescent brain. Using an animal model of adolescent intermittent ethanol [AIE; 5.0 g/kg, intragastric, 20 percent EtOH w/v; 2 days on/2 days off from postnatal day (P)25 to P55], we assessed the adult brain structural volumes and integrity on P80 and P220 using diffusion tensor imaging (DTI). While we did not observe a long-term effect of AIE on structural volumes, AIE did reduce axial diffusivity (AD) in the cerebellum, hippocampus and neocortex. Radial diffusivity (RD) was reduced in the hippocampus and neocortex of AIE-treated animals. Prior AIE treatment did not affect fractional anisotropy (FA), but did lead to long-term reductions of mean diffusivity (MD) in both the cerebellum and corpus callosum. AIE resulted in increased anxiety-like behavior and diminished object recognition memory, the latter of which was positively correlated with DTI measures. Across aging, whole brain volumes increased, as did volumes of the corpus callosum and neocortex. This was accompanied by age-associated AD reductions in the cerebellum and neocortex as well as RD and MD reductions in the cerebellum. Further, we found that FA increased in both the cerebellum and corpus callosum as rats aged from P80 to P220. Thus, both age and AIE treatment caused long-term changes to brain structural integrity that could contribute to cognitive dysfunction.

  1. A Neonate with Susceptibility to Long QT Syndrome Type 6 who Presented with Ventricular Fibrillation and Sudden Unexpected Infant Death.

    PubMed

    Sauer, Charles W; Marc-Aurele, Krishelle L

    2016-01-01

    BACKGROUND This is a case of a neonate with susceptibility to long QT syndrome (LQTS) who presented with a sudden unexpected infant death. Experts continue to debate whether universal electrocardiogram (ECG) screening of all newborns is feasible, practical, and cost-effective. CASE REPORT A 19-day-old neonate was found unresponsive by her mother. ECG showed ventricular fibrillation and a combination of a lidocaine drip plus multiple defibrillations converted the rhythm to normal sinus. Unfortunately, MRI brain imaging showed multiple infarcts and EEG showed burst suppression pattern with frequent seizures; life supportive treatment was stopped and the infant died. Genetic testing revealed two mutations in the KCNE2 gene consistent with susceptibility to LQTS type 6. CONCLUSIONS We believe this case is the first to demonstrate both a precipitating electrocardiographic and genetic cause of death for an infant with LQTS, showing a cause-and-effect relationship between LQTS mutation, ventricular arrhythmia, and death. We wonder whether universal ECG newborn screening to prevent LQTS death could have saved this baby. PMID:27465075

  2. A Neonate with Susceptibility to Long QT Syndrome Type 6 who Presented with Ventricular Fibrillation and Sudden Unexpected Infant Death

    PubMed Central

    Sauer, Charles W.; Marc-Aurele, Krishelle L.

    2016-01-01

    Patient: Female, 19-day Final Diagnosis: 19 day old neonate with susceptibility to Long QT syndrome • ventricular fibrillation Symptoms: Cardiac arrest • cardiac arrhythmia • encephalopathy Medication: — Clinical Procedure: Cardioversion Specialty: Pediatrics and Neonatology Objective: Rare disease Background: This is a case of a neonate with susceptibility to long QT syndrome (LQTS) who presented with a sudden unexpected infant death. Experts continue to debate whether universal electrocardiogram (ECG) screening of all newborns is feasible, practical, and cost-effective. Case Report: A 19-day-old neonate was found unresponsive by her mother. ECG showed ventricular fibrillation and a combination of a lidocaine drip plus multiple defibrillations converted the rhythm to normal sinus. Unfortunately, MRI brain imaging showed multiple infarcts and EEG showed burst suppression pattern with frequent seizures; life supportive treatment was stopped and the infant died. Genetic testing revealed two mutations in the KCNE2 gene consistent with susceptibility to LQTS type 6. Conclusions: We believe this case is the first to demonstrate both a precipitating electrocardiographic and genetic cause of death for an infant with LQTS, showing a cause-and-effect relationship between LQTS mutation, ventricular arrhythmia, and death. We wonder whether universal ECG newborn screening to prevent LQTS death could have saved this baby. PMID:27465075

  3. Vision's Brain.

    ERIC Educational Resources Information Center

    Miller, Julie Ann

    1978-01-01

    The functional architecture of the primary visual cortex has been explored by monitoring the responses of individual brain cells to visual stimuli. A combination of anatomical and physiological techniques reveals groups of functionally related cells, juxtaposed and superimposed, in a sometimes complex, but presumably efficient, structure. (BB)

  4. 42 CFR 493.861 - Standard; Unexpected antibody detection.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 5 2010-10-01 2010-10-01 false Standard; Unexpected antibody detection. 493.861 Section 493.861 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN..., Or Any Combination of These Tests § 493.861 Standard; Unexpected antibody detection. (a) Failure...

  5. Orthographic Processing and Visual Sequential Memory in Unexpectedly Poor Spellers

    ERIC Educational Resources Information Center

    Holmes, Virginia M.; Malone, Aisling M.; Redenbach, Holly

    2008-01-01

    Does unexpectedly poor spelling in adults result from inferior visual sequential memory? In one experiment, unexpectedly poor spellers performed significantly worse than better spellers in the immediate reproduction of sequences of visual symbols, but in a second experiment, the effect was not replicated. Poor spellers were also no worse at the…

  6. Unexpectedly Poor Spelling and Phonological-Processing Skill

    ERIC Educational Resources Information Center

    Holmes, Virginia M.; Quinn, Lisa

    2009-01-01

    This study investigated the phonological skills of university students who were unexpectedly poor spellers relative to their word reading accuracy. Compared with good spellers, unexpectedly poor spellers showed no deficits in phonological memory, selection of appropriate graphemes for phonemes in word misspellings and nonword spellings, and…

  7. 42 CFR 493.861 - Standard; Unexpected antibody detection.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 5 2011-10-01 2011-10-01 false Standard; Unexpected antibody detection. 493.861 Section 493.861 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN..., Or Any Combination of These Tests § 493.861 Standard; Unexpected antibody detection. (a) Failure...

  8. 42 CFR 493.861 - Standard; Unexpected antibody detection.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 5 2012-10-01 2012-10-01 false Standard; Unexpected antibody detection. 493.861 Section 493.861 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN..., Or Any Combination of These Tests § 493.861 Standard; Unexpected antibody detection. (a) Failure...

  9. 42 CFR 493.861 - Standard; Unexpected antibody detection.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 5 2014-10-01 2014-10-01 false Standard; Unexpected antibody detection. 493.861 Section 493.861 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN..., Or Any Combination of These Tests § 493.861 Standard; Unexpected antibody detection. (a) Failure...

  10. 3 CFR - Unexpected Urgent Refugee and Migration Needs

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 3 The President 1 2013-01-01 2013-01-01 false Unexpected Urgent Refugee and Migration Needs... Unexpected Urgent Refugee and Migration Needs Memorandum for the Secretary of State By the authority vested...) of the Migration and Refugee Assistance Act of 1962 (the “Act”), as amended, (22 U.S.C....

  11. 3 CFR - Unexpected Urgent Refugee and Migration Needs

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 3 The President 1 2013-01-01 2013-01-01 false Unexpected Urgent Refugee and Migration Needs Presidential Documents Other Presidential Documents Presidential Determination No. 2012-12 of July 12, 2012 Unexpected Urgent Refugee and Migration Needs Memorandum for the Secretary of State By the authority vested in me as President by the...

  12. Discovering novel microRNAs and age-related nonlinear changes in rat brains using deep sequencing.

    PubMed

    Yin, Lanxuan; Sun, Yubai; Wu, Jinfeng; Yan, Siyu; Deng, Zhenglu; Wang, Jun; Liao, Shenke; Yin, Dazhong; Li, Guolin

    2015-02-01

    Elucidating the molecular mechanisms of brain aging remains a significant challenge for biogerontologists. The discovery of gene regulation by microRNAs (miRNAs) has added a new dimension for examining this process; however, the full complement of miRNAs involved in brain aging is still not known. In this study, miRNA profiles of young, adult, and old rats were obtained to evaluate molecular changes during aging. High-throughput deep sequencing revealed 547 known and 171 candidate novel miRNAs that were differentially expressed among groups. Unexpectedly, miRNA expression did not decline progressively with advancing age; moreover, genes targeted by age-associated miRNAs were predicted to be involved in biological processes linked to aging and neurodegenerative diseases. These findings provide novel insight into the molecular mechanisms underlying brain aging and a resource for future studies on age-related brain disorders.

  13. MaxiK channel interactome reveals its interaction with GABA transporter 3 and heat shock protein 60 in the mammalian brain.

    PubMed

    Singh, H; Li, M; Hall, L; Chen, S; Sukur, S; Lu, R; Caputo, A; Meredith, A L; Stefani, E; Toro, L

    2016-03-11

    Large conductance voltage and calcium-activated potassium (MaxiK) channels are activated by membrane depolarization and elevated cytosolic Ca(2+). In the brain, they localize to neurons and astrocytes, where they play roles such as resetting the membrane potential during an action potential, neurotransmitter release, and neurovascular coupling. MaxiK channels are known to associate with several modulatory proteins and accessory subunits, and each of these interactions can have distinct physiological consequences. To uncover new players in MaxiK channel brain physiology, we applied a directed proteomic approach and obtained MaxiK channel pore-forming α subunit brain interactome using specific antibodies. Controls included immunoprecipitations with rabbit immunoglobulin G (IgG) and with anti-MaxiK antibodies in wild type and MaxiK channel knockout mice (Kcnma1(-/-)), respectively. We have found known and unreported interactive partners that localize to the plasma membrane, extracellular space, cytosol and intracellular organelles including mitochondria, nucleus, endoplasmic reticulum and Golgi apparatus. Localization of MaxiK channel to mitochondria was further confirmed using purified brain mitochondria colabeled with MitoTracker. Independent proof of MaxiK channel interaction with previously unidentified partners is given for GABA transporter 3 (GAT3) and heat shock protein 60 (HSP60). In human embryonic kidney 293 cells containing SV40 T-antigen (HEK293T) cells, both GAT3 and HSP60 coimmunoprecipitated and colocalized with MaxiK channel; colabeling was observed mainly at the cell periphery with GAT3 and intracellularly with HSP60 with protein proximity indices of ∼ 0.6 and ∼ 0.4, respectively. In rat primary hippocampal neurons, colocalization index was identical for GAT3 (∼ 0.6) and slightly higher for HSP60 (∼ 0.5) association with MaxiK channel. The results of this study provide a complete interactome of MaxiK channel the mouse brain, further establish

  14. Lead intoxication from an unexpected source. [Fruit drink dispensers

    SciTech Connect

    Kleinfeld, M.J.

    1982-02-01

    A case of lead intoxication from an unexpected source is reported. An 18-year-old man came to the Divisin of Safety and Health, New York City, complaining of periodic cramping abdominal pain and weakness of several weeks' duration. In view of clinical laboratory findings, lead intoxication was considered in the differential diagnosis and determination of blood lead and urinary amino levulinic acid (ALA) were done. The blood lead value was 70 ..mu..g/100 g of whole blood. The urinary ALA value was 3.61 mg/100 of creatinine (normal, < 2.0 mg/100 mg of creatinine). A repeated urinary ALA test on the following day gave a value of 3.50 mg/100 mg of creatinine. An industrial hygiene survey was made to ascertain the patient's exposure to lead. The work place was a luncheonette that served flavored fruit drinks. The fruit drinks were dispensed from 12 tanks, and a sampling of these tanks showed that six of them were made of metal and had been soldered in the past. In one tank a chunk of lead was found. An analysis of this chunk of lead revealed that the lead content was 50.1%. Only two of the 12 tanks showed levels of lead that were excessively high; these were made of metal and had been soldered in the past. It was recommended to the owner that acid-containing drinks should be stored in tanks constructed of stainless steel,plastic, or other lead-free materials.

  15. Bah humbug: Unexpected Christmas cards and the reciprocity norm.

    PubMed

    Meier, Brian P

    2016-01-01

    The reciprocity norm refers to the expectation that people will help those who helped them. A well-known study revealed that the norm is strong with Christmas cards, with 20% of people reciprocating a Christmas card received from a stranger. I attempted to conceptually replicate and extend this effect. In Study 1, 755 participants received a Christmas card supposedly from a more- versus less-similar stranger. The reciprocation rate was unexpectedly low (2%), which did not allow for a test of a similarity effect. Two potential reasons for this low rate were examined in Study 2 in which 494 participants reported their likelihood of reciprocating a Christmas card from a stranger as well as their felt suspicions/threat about the card and their frequency of e-mail use. Reciprocation likelihood was negatively correlated with perceived threat/suspicion and e-mail use. It appears that reciprocating a gift from a stranger in offline settings may be less likely than expected. PMID:26666577

  16. Bah humbug: Unexpected Christmas cards and the reciprocity norm.

    PubMed

    Meier, Brian P

    2016-01-01

    The reciprocity norm refers to the expectation that people will help those who helped them. A well-known study revealed that the norm is strong with Christmas cards, with 20% of people reciprocating a Christmas card received from a stranger. I attempted to conceptually replicate and extend this effect. In Study 1, 755 participants received a Christmas card supposedly from a more- versus less-similar stranger. The reciprocation rate was unexpectedly low (2%), which did not allow for a test of a similarity effect. Two potential reasons for this low rate were examined in Study 2 in which 494 participants reported their likelihood of reciprocating a Christmas card from a stranger as well as their felt suspicions/threat about the card and their frequency of e-mail use. Reciprocation likelihood was negatively correlated with perceived threat/suspicion and e-mail use. It appears that reciprocating a gift from a stranger in offline settings may be less likely than expected.

  17. Competition can lead to unexpected patterns in tropical ant communities

    NASA Astrophysics Data System (ADS)

    Ellwood, M. D. Farnon; Blüthgen, Nico; Fayle, Tom M.; Foster, William A.; Menzel, Florian

    2016-08-01

    Ecological communities are structured by competitive, predatory, mutualistic and parasitic interactions combined with chance events. Separating deterministic from stochastic processes is possible, but finding statistical evidence for specific biological interactions is challenging. We attempt to solve this problem for ant communities nesting in epiphytic bird's nest ferns (Asplenium nidus) in Borneo's lowland rainforest. By recording the frequencies with which each and every single ant species occurred together, we were able to test statistically for patterns associated with interspecific competition. We found evidence for competition, but the resulting co-occurrence pattern was the opposite of what we expected. Rather than detecting species segregation-the classical hallmark of competition-we found species aggregation. Moreover, our approach of testing individual pairwise interactions mostly revealed spatially positive rather than negative associations. Significant negative interactions were only detected among large ants, and among species of the subfamily Ponerinae. Remarkably, the results from this study, and from a corroborating analysis of ant communities known to be structured by competition, suggest that competition within the ants leads to species aggregation rather than segregation. We believe this unexpected result is linked with the displacement of species following asymmetric competition. We conclude that analysing co-occurrence frequencies across complete species assemblages, separately for each species, and for each unique pairwise combination of species, represents a subtle yet powerful way of detecting structure and compartmentalisation in ecological communities.

  18. Cerebral complexity preceded enlarged brain size and reduced olfactory bulbs in Old World monkeys

    PubMed Central

    Gonzales, Lauren A.; Benefit, Brenda R.; McCrossin, Monte L.; Spoor, Fred

    2015-01-01

    Analysis of the only complete early cercopithecoid (Old World monkey) endocast currently known, that of 15-million-year (Myr)-old Victoriapithecus, reveals an unexpectedly small endocranial volume (ECV) relative to body size and a large olfactory bulb volume relative to ECV, similar to extant lemurs and Oligocene anthropoids. However, the Victoriapithecus brain has principal and arcuate sulci of the frontal lobe not seen in the stem catarrhine Aegyptopithecus, as well as a distinctive cercopithecoid pattern of gyrification, indicating that cerebral complexity preceded encephalization in cercopithecoids. Since larger ECVs, expanded frontal lobes, and reduced olfactory bulbs are already present in the 17- to 18-Myr-old ape Proconsul these features evolved independently in hominoids (apes) and cercopithecoids and much earlier in the former. Moreover, the order of encephalization and brain reorganization was apparently different in hominoids and cercopithecoids, showing that brain size and cerebral organization evolve independently. PMID:26138795

  19. Role of organic cation transporters (OCTs) in the brain.

    PubMed

    Couroussé, Thomas; Gautron, Sophie

    2015-02-01

    Organic cation transporters (OCTs) are polyspecific facilitated diffusion transporters that contribute to the absorption and clearance of various physiological compounds and xenobiotics in mammals, by mediating their vectorial transport in kidney, liver or placenta cells. Unexpectedly, a corpus of studies within the last decade has revealed that these transporters also fulfill important functions within the brain. The high-affinity monoamine reuptake transporters (SERT, NET and DAT) exert a crucial role in the control of aminergic transmission by ensuring the rapid clearance of the released transmitters from the synaptic cleft and their recycling into the nerve endings. Substantiated evidence indicate that OCTs may serve in the brain as a compensatory clearance system in case of monoamine spillover after high-affinity transporter blockade by antidepressants or psychostimulants, and in areas of lower high-affinity transporter density at distance from the aminergic varicosities. In spite of similar anatomical profiles, the two brain OCTs, OCT2 and OCT3, show subtle differences in their distribution in the brain and their functional properties. These transporters contribute to shape a variety of central functions related to mood such as anxiety, response to stress and antidepressant efficacy, but are also implicated in other processes like osmoregulation and neurotoxicity. In this review, we discuss the recent knowledge and emerging concepts on the role of OCTs in the uptake of aminergic neurotransmitters in the brain and in these various physiological functions, focusing on the implications for mental health. PMID:25251364

  20. A brain slice culture model of viral encephalitis reveals an innate CNS cytokine response profile and the therapeutic potential of caspase inhibition

    PubMed Central

    Dionne, Kalen R.; Leser, J. Smith; Lorenzen, Kristi A.; Beckham, J. David; Tyler, Kenneth L.

    2011-01-01

    Viral encephalitis is a significant cause of human morbidity and mortality in large part due to suboptimal diagnosis and treatment. Murine reovirus infection serves as a classic experimental model of viral encephalitis. Infection of neonatal mice with T3 reoviruses results in lethal encephalitis associated with neuronal infection, apoptosis, and CNS tissue injury. We have developed an ex vivo brain slice culture (BSC) system that recapitulates the basic pathological features and kinetics of viral replication seen in vivo. We utilize the BSC model to identify an innate, brain-tissue specific inflammatory cytokine response to reoviral infection, which is characterized by the release of IL6, CXCL10, RANTES, and murine IL8 analog (KC). Additionally, we demonstrate the potential utility of this system as a pharmaceutical screening platform by inhibiting reovirus-induced apoptosis and CNS tissue injury with the pan-caspase inhibitor, Q-VD-OPh. Cultured brain slices not only serve to model events occurring during viral encephalitis, but can also be utilized to investigate aspects of pathogenesis and therapy that are not experimentally accessible in vivo. PMID:21241693

  1. High-Field MRI Reveals a Drastic Increase of Hypoxia-Induced Microhemorrhages upon Tissue Reoxygenation in the Mouse Brain with Strong Predominance in the Olfactory Bulb

    PubMed Central

    Helluy, Xavier; Milford, David; Heiland, Sabine; Bendszus, Martin

    2016-01-01

    Human pathophysiology of high altitude hypoxic brain injury is not well understood and research on the underlying mechanisms is hampered by the lack of well-characterized animal models. In this study, we explored the evolution of brain injury by magnetic resonance imaging (MRI) and histological methods in mice exposed to normobaric hypoxia at 8% oxygen for 48 hours followed by rapid reoxygenation and incubation for further 24 h under normoxic conditions. T2*-, diffusion-weighted and T2-relaxometry MRI was performed before exposure, immediately after 48 hours of hypoxia and 24 hours after reoxygenation. Cerebral microhemorrhages, previously described in humans suffering from severe high altitude cerebral edema, were also detected in mice upon hypoxia-reoxygenation with a strong region-specific clustering in the olfactory bulb, and to a lesser extent, in the basal ganglia and cerebral white matter. The number of microhemorrhages determined immediately after hypoxia was low, but strongly increased 24 hours upon onset of reoxygenation. Histologically verified microhemorrhages were exclusively located around cerebral microvessels with disrupted interendothelial tight junction protein ZO-1. In contrast, quantitative T2 and apparent-diffusion-coefficient values immediately after hypoxia and after 24 hours of reoxygenation did not show any region-specific alteration, consistent with subtle multifocal but not with regional or global brain edema. PMID:26863147

  2. High-Field MRI Reveals a Drastic Increase of Hypoxia-Induced Microhemorrhages upon Tissue Reoxygenation in the Mouse Brain with Strong Predominance in the Olfactory Bulb.

    PubMed

    Hoffmann, Angelika; Kunze, Reiner; Helluy, Xavier; Milford, David; Heiland, Sabine; Bendszus, Martin; Pham, Mirko; Marti, Hugo H

    2016-01-01

    Human pathophysiology of high altitude hypoxic brain injury is not well understood and research on the underlying mechanisms is hampered by the lack of well-characterized animal models. In this study, we explored the evolution of brain injury by magnetic resonance imaging (MRI) and histological methods in mice exposed to normobaric hypoxia at 8% oxygen for 48 hours followed by rapid reoxygenation and incubation for further 24 h under normoxic conditions. T2*-, diffusion-weighted and T2-relaxometry MRI was performed before exposure, immediately after 48 hours of hypoxia and 24 hours after reoxygenation. Cerebral microhemorrhages, previously described in humans suffering from severe high altitude cerebral edema, were also detected in mice upon hypoxia-reoxygenation with a strong region-specific clustering in the olfactory bulb, and to a lesser extent, in the basal ganglia and cerebral white matter. The number of microhemorrhages determined immediately after hypoxia was low, but strongly increased 24 hours upon onset of reoxygenation. Histologically verified microhemorrhages were exclusively located around cerebral microvessels with disrupted interendothelial tight junction protein ZO-1. In contrast, quantitative T2 and apparent-diffusion-coefficient values immediately after hypoxia and after 24 hours of reoxygenation did not show any region-specific alteration, consistent with subtle multifocal but not with regional or global brain edema. PMID:26863147

  3. Bilinguals at the "cocktail party": dissociable neural activity in auditory-linguistic brain regions reveals neurobiological basis for nonnative listeners' speech-in-noise recognition deficits.

    PubMed

    Bidelman, Gavin M; Dexter, Lauren

    2015-04-01

    We examined a consistent deficit observed in bilinguals: poorer speech-in-noise (SIN) comprehension for their nonnative language. We recorded neuroelectric mismatch potentials in mono- and bi-lingual listeners in response to contrastive speech sounds in noise. Behaviorally, late bilinguals required ∼10dB more favorable signal-to-noise ratios to match monolinguals' SIN abilities. Source analysis of cortical activity demonstrated monotonic increase in response latency with noise in superior temporal gyrus (STG) for both groups, suggesting parallel degradation of speech representations in auditory cortex. Contrastively, we found differential speech encoding between groups within inferior frontal gyrus (IFG)-adjacent to Broca's area-where noise delays observed in nonnative listeners were offset in monolinguals. Notably, brain-behavior correspondences double dissociated between language groups: STG activation predicted bilinguals' SIN, whereas IFG activation predicted monolinguals' performance. We infer higher-order brain areas act compensatorily to enhance impoverished sensory representations but only when degraded speech recruits linguistic brain mechanisms downstream from initial auditory-sensory inputs.

  4. Audit of practice in sudden unexpected death in epilepsy (SUDEP) post mortems and neuropathological findings

    PubMed Central

    Michalak, Zuzanna; Wright, Gabriella; Dawson, Timothy; Hilton, David; Joshi, Abhijit; Diehl, Beate; Koepp, Matthias; Lhatoo, Samden; Sander, Josemir W.; Sisodiya, Sanjay M.

    2015-01-01

    Aims Sudden unexpected death in epilepsy (SUDEP) is one of the leading causes of death in people with epilepsy. For classification of definite SUDEP, a post mortem (PM), including anatomical and toxicological examination, is mandatory to exclude other causes of death. We audited PM practice as well as the value of brain examination in SUDEP. Methods We reviewed 145 PM reports in SUDEP cases from four UK neuropathology centres. Data were extracted for clinical epilepsy details, circumstances of death and neuropathological findings. Results Macroscopic brain abnormalities were identified in 52% of cases. Mild brain swelling was present in 28%, and microscopic pathologies relevant to cause or effect of seizures were seen in 89%. Examination based on whole fixed brains (76.6% of all PMs), and systematic regional sampling was associated with higher detection rates of underlying pathology (P < 0.01). Information was more frequently recorded regarding circumstances of death and body position/location than clinical epilepsy history and investigations. Conclusion Our findings support the contribution of examination of the whole fixed brain in SUDEP, with high rates of detection of relevant pathology. Availability of full clinical epilepsy‐related information at the time of PM could potentially further improve detection through targeted tissue sampling. Apart from confirmation of SUDEP, complete neuropathological examination contributes to evaluation of risk factors as well as helping to direct future research into underlying causes. PMID:26300477

  5. Quantitative proteomics reveals protein-protein interactions with fibroblast growth factor 12 as a component of the voltage-gated sodium channel 1.2 (nav1.2) macromolecular complex in Mammalian brain.

    PubMed

    Wildburger, Norelle C; Ali, Syed R; Hsu, Wei-Chun J; Shavkunov, Alexander S; Nenov, Miroslav N; Lichti, Cheryl F; LeDuc, Richard D; Mostovenko, Ekaterina; Panova-Elektronova, Neli I; Emmett, Mark R; Nilsson, Carol L; Laezza, Fernanda

    2015-05-01

    Voltage-gated sodium channels (Nav1.1-Nav1.9) are responsible for the initiation and propagation of action potentials in neurons, controlling firing patterns, synaptic transmission and plasticity of the brain circuit. Yet, it is the protein-protein interactions of the macromolecular complex that exert diverse modulatory actions on the channel, dictating its ultimate functional outcome. Despite the fundamental role of Nav channels in the brain, information on its proteome is still lacking. Here we used affinity purification from crude membrane extracts of whole brain followed by quantitative high-resolution mass spectrometry to resolve the identity of Nav1.2 protein interactors. Of the identified putative protein interactors, fibroblast growth factor 12 (FGF12), a member of the nonsecreted intracellular FGF family, exhibited 30-fold enrichment in Nav1.2 purifications compared with other identified proteins. Using confocal microscopy, we visualized native FGF12 in the brain tissue and confirmed that FGF12 forms a complex with Nav1.2 channels at the axonal initial segment, the subcellular specialized domain of neurons required for action potential initiation. Co-immunoprecipitation studies in a heterologous expression system validate Nav1.2 and FGF12 as interactors, whereas patch-clamp electrophysiology reveals that FGF12 acts synergistically with CaMKII, a known kinase regulator of Nav channels, to modulate Nav1.2-encoded currents. In the presence of CaMKII inhibitors we found that FGF12 produces a bidirectional shift in the voltage-dependence of activation (more depolarized) and the steady-state inactivation (more hyperpolarized) of Nav1.2, increasing the channel availability. Although providing the first characterization of the Nav1.2 CNS proteome, we identify FGF12 as a new functionally relevant interactor. Our studies will provide invaluable information to parse out the molecular determinant underlying neuronal excitability and plasticity, and extending the

  6. Brain-specific Phgdh deletion reveals a pivotal role for L-serine biosynthesis in controlling the level of D-serine, an N-methyl-D-aspartate receptor co-agonist, in adult brain.

    PubMed

    Yang, Jung Hoon; Wada, Akira; Yoshida, Kazuyuki; Miyoshi, Yurika; Sayano, Tomoko; Esaki, Kayoko; Kinoshita, Masami O; Tomonaga, Shozo; Azuma, Norihiro; Watanabe, Masahiko; Hamase, Kenji; Zaitsu, Kiyoshi; Machida, Takeo; Messing, Albee; Itohara, Shigeyoshi; Hirabayashi, Yoshio; Furuya, Shigeki

    2010-12-31

    In mammalian brain, D-serine is synthesized from L-serine by serine racemase, and it functions as an obligatory co-agonist at the glycine modulatory site of N-methyl-D-aspartate (NMDA)-selective glutamate receptors. Although diminution in D-serine level has been implicated in NMDA receptor hypofunction, which is thought to occur in schizophrenia, the source of the precursor L-serine and its role in D-serine metabolism in adult brain have yet to be determined. We investigated whether L-serine synthesized in brain via the phosphorylated pathway is essential for D-serine synthesis by generating mice with a conditional deletion of D-3-phosphoglycerate dehydrogenase (Phgdh; EC 1.1.1.95). This enzyme catalyzes the first step in L-serine synthesis via the phosphorylated pathway. HPLC analysis of serine enantiomers demonstrated that both L- and D-serine levels were markedly decreased in the cerebral cortex and hippocampus of conditional knock-out mice, whereas the serine deficiency did not alter protein expression levels of serine racemase and NMDA receptor subunits in these regions. The present study provides definitive proof that L-serine-synthesized endogenously via the phosphorylated pathway is a key rate-limiting factor for maintaining steady-state levels of D-serine in adult brain. Furthermore, NMDA-evoked transcription of Arc, an immediate early gene, was diminished in the hippocampus of conditional knock-out mice. Thus, this study demonstrates that in mature neuronal circuits L-serine availability determines the rate of D-serine synthesis in the forebrain and controls NMDA receptor function at least in the hippocampus. PMID:20966073

  7. Forward shift of feeding buzz components of dolphins and belugas during associative learning reveals a likely connection to reward expectation, pleasure and brain dopamine activation.

    PubMed

    Ridgway, S H; Moore, P W; Carder, D A; Romano, T A

    2014-08-15

    For many years, we heard sounds associated with reward from dolphins and belugas. We named these pulsed sounds victory squeals (VS), as they remind us of a child's squeal of delight. Here we put these sounds in context with natural and learned behavior. Like bats, echolocating cetaceans produce feeding buzzes as they approach and catch prey. Unlike bats, cetaceans continue their feeding buzzes after prey capture and the after portion is what we call the VS. Prior to training (or conditioning), the VS comes after the fish reward; with repeated trials it moves to before the reward. During training, we use a whistle or other sound to signal a correct response by the animal. This sound signal, named a secondary reinforcer (SR), leads to the primary reinforcer, fish. Trainers usually name their whistle or other SR a bridge, as it bridges the time gap between the correct response and reward delivery. During learning, the SR becomes associated with reward and the VS comes after the SR rather than after the fish. By following the SR, the VS confirms that the animal expects a reward. Results of early brain stimulation work suggest to us that SR stimulates brain dopamine release, which leads to the VS. Although there are no direct studies of dopamine release in cetaceans, we found that the timing of our VS is consistent with a response after dopamine release. We compared trained vocal responses to auditory stimuli with VS responses to SR sounds. Auditory stimuli that did not signal reward resulted in faster responses by a mean of 151 ms for dolphins and 250 ms for belugas. In laboratory animals, there is a 100 to 200 ms delay for dopamine release. VS delay in our animals is similar and consistent with vocalization after dopamine release. Our novel observation suggests that the dopamine reward system is active in cetacean brains. PMID:25122919

  8. Brain activity mapping in Mecp2 mutant mice reveals functional deficits in forebrain circuits, including key nodes in the default mode network, that are reversed with ketamine treatment.

    PubMed

    Kron, Miriam; Howell, C James; Adams, Ian T; Ransbottom, Michael; Christian, Diana; Ogier, Michael; Katz, David M

    2012-10-01

    Excitatory-inhibitory imbalance has been identified within specific brain microcircuits in models of Rett syndrome (RTT) and other autism spectrum disorders (ASDs). However, macrocircuit dysfunction across the RTT brain as a whole has not been defined. To approach this issue, we mapped expression of the activity-dependent, immediate-early gene product Fos in the brains of wild-type (Wt) and methyl-CpG-binding protein 2 (Mecp2)-null (Null) mice, a model of RTT, before and after the appearance of overt symptoms (3 and 6 weeks of age, respectively). At 6 weeks, Null mice exhibit significantly less Fos labeling than Wt in limbic cortices and subcortical structures, including key nodes in the default mode network. In contrast, Null mice exhibit significantly more Fos labeling than Wt in the hindbrain, most notably in cardiorespiratory regions of the nucleus tractus solitarius (nTS). Using nTS as a model, whole-cell recordings demonstrated that increased Fos expression in Nulls at 6 weeks of age is associated with synaptic hyperexcitability, including increased frequency of spontaneous and miniature EPSCs and increased amplitude of evoked EPSCs in Nulls. No such effect of genotype on Fos or synaptic function was seen at 3 weeks. In the mutant forebrain, reduced Fos expression, as well as abnormal sensorimotor function, were reversed by the NMDA receptor antagonist ketamine. In light of recent findings that the default mode network is hypoactive in autism, our data raise the possibility that hypofunction within this meta-circuit is a shared feature of RTT and other ASDs and is reversible. PMID:23035095

  9. ZENK labeling within social behavior brain regions reveals breeding context-dependent patterns of neural activity associated with song in male European starlings (Sturnus vulgaris)

    PubMed Central

    Heimovics, Sarah A.; Riters, Lauren V.

    2007-01-01

    In songbirds, song learning and production are regulated by the song control system. How the rest of the brain interacts with song nuclei to ensure that song is produced in an appropriate context is not yet clear. In male European starlings (Sturnus vulgaris), breeding context song is sexually motivated whereas non-breeding context song is more broadly socially motivated. Brain regions involved in regulating social behavior might differentially regulate starling song depending upon the context in which it is produced. Here, we compared the number of ZENK-labeled cells in song and social behavior nuclei in starlings singing in either a breeding or a non-breeding context. Numbers of ZENK-labeled cells in HVC related positively to song produced in both contexts. Interestingly, numbers of ZENK-labeled cells in one subdivision of the lateral septum (LS) related negatively to breeding context song but positively to non-breeding context song. In a subdivision of the medial bed nucleus of the stria terminalis (BSTm) ZENK labeling only related positively to non-breeding context song whereas in the ventromedial nucleus of the hypothalamus (VMH) ZENK labeling showed a tighter positive relationship with breeding context song. Together, these findings indicate that social behavior brain regions outside of the song control system regulate singing behavior differently depending upon whether song is sexually or more broadly socially motivated. Breeding context-dependent regulation of song by LS, BSTm, and VMH suggests that these nuclei may be central to adjusting song production so that it occurs in response to appropriate social and environmental stimuli. PMID:17113163

  10. ZENK labeling within social behavior brain regions reveals breeding context-dependent patterns of neural activity associated with song in male European starlings (Sturnus vulgaris).

    PubMed

    Heimovics, Sarah A; Riters, Lauren V

    2007-01-25

    In songbirds, song learning and production are regulated by the song control system. How the rest of the brain interacts with song nuclei to ensure that song is produced in an appropriate context is not yet clear. In male European starlings (Sturnus vulgaris), breeding context song is sexually motivated, whereas, non-breeding context song is more broadly socially motivated. Brain regions involved in regulating social behavior might differentially regulate starling song depending upon the context in which it is produced. Here, we compared the number of ZENK-labeled cells in song and social behavior nuclei in starlings singing in either a breeding or a non-breeding context. Numbers of ZENK-labeled cells in HVC related positively to song produced in both contexts. Interestingly, numbers of ZENK-labeled cells in one subdivision of the lateral septum (LS) related negatively to breeding context song but positively to non-breeding context song. In a subdivision of the medial bed nucleus of the stria terminalis (BSTm) ZENK labeling only related positively to non-breeding context song, whereas, in the ventromedial nucleus of the hypothalamus (VMH) ZENK labeling showed a tighter positive relationship with breeding context song. Together, these findings indicate that social behavior brain regions outside of the song control system regulate singing behavior differently depending upon whether song is sexually or more broadly socially motivated. Breeding context-dependent regulation of song by LS, BSTm, and VMH suggests that these nuclei may be central to adjusting song production so that it occurs in response to appropriate social and environmental stimuli. PMID:17113163

  11. Assessment of the structural brain network reveals altered connectivity in children with unilateral cerebral palsy due to periventricular white matter lesions

    PubMed Central

    Pannek, Kerstin; Boyd, Roslyn N.; Fiori, Simona; Guzzetta, Andrea; Rose, Stephen E.

    2014-01-01

    Background Cerebral palsy (CP) is a term to describe the spectrum of disorders of impaired motor and sensory function caused by a brain lesion occurring early during development. Diffusion MRI and tractography have been shown to be useful in the study of white matter (WM) microstructure in tracts likely to be impacted by the static brain lesion. Aim The purpose of this study was to identify WM pathways with altered connectivity in children with unilateral CP caused by periventricular white matter lesions using a whole-brain connectivity approach. Methods Data of 50 children with unilateral CP caused by periventricular white matter lesions (5–17 years; manual ability classification system [MACS] I = 25/II = 25) and 17 children with typical development (CTD; 7–16 years) were analysed. Structural and High Angular Resolution Diffusion weighted Images (HARDI; 64 directions, b = 3000 s/mm2) were acquired at 3 T. Connectomes were calculated using whole-brain probabilistic tractography in combination with structural parcellation of the cortex and subcortical structures. Connections with altered fractional anisotropy (FA) in children with unilateral CP compared to CTD were identified using network-based statistics (NBS). The relationship between FA and performance of the impaired hand in bimanual tasks (Assisting Hand Assessment—AHA) was assessed in connections that showed significant differences in FA compared to CTD. Results FA was reduced in children with unilateral CP compared to CTD. Seven pathways, including the corticospinal, thalamocortical, and fronto-parietal association pathways were identified simultaneously in children with left and right unilateral CP. There was a positive relationship between performance of the impaired hand in bimanual tasks and FA within the cortico-spinal and thalamo-cortical pathways (r2 = 0.16–0.44; p < 0.05). Conclusion This study shows that network-based analysis of structural connectivity can identify alterations

  12. The canadian sludge irradiator project: Unexpected challenges and opportunities

    NASA Astrophysics Data System (ADS)

    Swinwood, Jean F.; Fraser, Frank M.

    1995-09-01

    Since 1991, Nordion International has been seeking approval of a proposal to treat municipal sewage sludge using a cobalt 60 sourced tote box irradiator, at a Sludge Recycling Facility. The two-year approval process followed the expected path of reviews by technical and financial experts, processing field trials, market studies and political deliberations. The result was a number of unexpected challenges, and even opportunities. This paper discusses some of these unexpected aspects of the project.

  13. Sudden unexpected death in epilepsy: an important concern

    PubMed Central

    Scorza, Fulvio Alexandre; Cysneiros, Roberta Monterazzo; de Albuquerque, Marly; Scattolini, Marcello; Arida, Ricardo Mario

    2011-01-01

    Epilepsy is one of the most common neurologic problems worldwide. Unfortunately, individuals with epilepsy are at higher risk of death than the general population, and sudden unexpected death in epilepsy is the most important direct epilepsy-related cause of death. In this review article, our research group focused on the risk factors, mechanisms and preventative measures obtained from clinical and experimental studies on sudden unexpected death in epilepsy. PMID:21779724

  14. Metabolomic Profiling of Post-Mortem Brain Reveals Changes in Amino Acid and Glucose Metabolism in Mental Illness Compared with Controls.

    PubMed

    Zhang, Rong; Zhang, Tong; Ali, Ali Muhsen; Al Washih, Mohammed; Pickard, Benjamin; Watson, David G

    2016-01-01

    Metabolomic profiling was carried out on 53 post-mortem brain samples from subjects diagnosed with schizophrenia, depression, bipolar disorder (SDB), diabetes, and controls. Chromatography on a ZICpHILIC column was used with detection by Orbitrap mass spectrometry. Data extraction was carried out with m/z Mine 2.14 with metabolite searching against an in-house database. There was no clear discrimination between the controls and the SDB samples on the basis of a principal components analysis (PCA) model of 755 identified or putatively identified metabolites. Orthogonal partial least square discriminant analysis (OPLSDA) produced clear separation between 17 of the controls and 19 of the SDB samples (R2CUM 0.976, Q2 0.671, p-value of the cross-validated ANOVA score 0.0024). The most important metabolites producing discrimination were the lipophilic amino acids leucine/isoleucine, proline, methionine, phenylalanine, and tyrosine; the neurotransmitters GABA and NAAG and sugar metabolites sorbitol, gluconic acid, xylitol, ribitol, arabinotol, and erythritol. Eight samples from diabetic brains were analysed, six of which grouped with the SDB samples without compromising the model (R2 CUM 0.850, Q2 CUM 0.534, p-value for cross-validated ANOVA score 0.00087). There appears on the basis of this small sample set to be some commonality between metabolic perturbations resulting from diabetes and from SDB. PMID:27076878

  15. A comparative examination of neural circuit and brain patterning between the lamprey and amphioxus reveals the evolutionary origin of the vertebrate visual center.

    PubMed

    Suzuki, Daichi G; Murakami, Yasunori; Escriva, Hector; Wada, Hiroshi

    2015-02-01

    Vertebrates are equipped with so-called camera eyes, which provide them with image-forming vision. Vertebrate image-forming vision evolved independently from that of other animals and is regarded as a key innovation for enhancing predatory ability and ecological success. Evolutionary changes in the neural circuits, particularly the visual center, were central for the acquisition of image-forming vision. However, the evolutionary steps, from protochordates to jaw-less primitive vertebrates and then to jawed vertebrates, remain largely unknown. To bridge this gap, we present the detailed development of retinofugal projections in the lamprey, the neuroarchitecture in amphioxus, and the brain patterning in both animals. Both the lateral eye in larval lamprey and the frontal eye in amphioxus project to a light-detecting visual center in the caudal prosencephalic region marked by Pax6, which possibly represents the ancestral state of the chordate visual system. Our results indicate that the visual system of the larval lamprey represents an evolutionarily primitive state, forming a link from protochordates to vertebrates and providing a new perspective of brain evolution based on developmental mechanisms and neural functions.

  16. Alterations of the intracellular water and ion concentrations in brain and liver cells during aging as revealed by energy dispersive X-ray microanalysis of bulk specimens

    SciTech Connect

    Lustyik, G.; Nagy, I.

    1985-01-01

    Age dependence of the intracellular concentrations of monovalent ions (Na+, K+ and Cl-) was examined in 1, 11 and 25-month-old rat brain and liver cells by using energy dispersive X-ray microanalysis. The in vivo concentrations of Na+, K+ and Cl- ions were calculated from two different measurements: The elemental concentrations were measured in freeze-dried tissue pieces, and the intracellular water content was determined by means of a recently developed X-ray microanalytic method, using frozen-hydrated and fractured bulk specimens as well as subsequent freeze-drying. All the single monovalent ion concentrations and consequently, also the total monovalent ion content showed statistically significant increases during aging in brain cortical neurons. A 3-6% loss of the intracellular water content was accompanied by a 25-45% increase of the monovalent ionic strengths by the age of 25 months. A membrane protective OH radical scavenger (centrophenoxine) reversed the dehydration in the nerve cells of old animals, resulting in a decrease of the intracellular ion concentrations. Aging has a less prominent effect on the water and ion contents of the hepatocytes. The degree of water loss of cytoplasm exceeds that of the nuclei in the liver, suggesting that dominantly the translational steps can be involved in the general age altered slowing down of the protein synthetic machinery, predicted by the membrane hypothesis of aging.

  17. Interferon-gamma-responsive neuronal sites in the normal rat brain: receptor protein distribution and cell activation revealed by Fos induction.

    PubMed

    Robertson, B; Kong, G; Peng, Z; Bentivoglio, M; Kristensson, K

    2000-05-01

    Constitutive expression of the interferon-gamma receptor protein (IFN-gammaR), and the distribution of cells in which Fos, a marker of cell activation, is induced by intracerebroventricular administration of IFN-gamma, were studied in the rat brain by immunohistochemistry. IFN-gammaR immunopositivity was found in neuronal elements, which exhibited a selective distribution being concentrated in the piriform and entorhinal cortex, midline thalamus and medial hypothalamic structures, brainstem nociceptive relays (including the periaqueductal gray, the parabrachial nuclei and the caudal part of the spinal trigeminal nuclei), and circumventricular organs such as the median eminence and area postrema. IFN-gamma-induced Fos expression mostly corresponded to neuronal sites of receptor distribution. Because of its topographical distribution, it is suggested that activation of the IFN-gammaR in neurons may play a role to limit spread of infections in the brain and, in concert with other proinflammatory cytokines, to modulate adaptive responses to an antigen challenge mediated by the central nervous system. PMID:10779704

  18. A comparative examination of neural circuit and brain patterning between the lamprey and amphioxus reveals the evolutionary origin of the vertebrate visual center.

    PubMed

    Suzuki, Daichi G; Murakami, Yasunori; Escriva, Hector; Wada, Hiroshi

    2015-02-01

    Vertebrates are equipped with so-called camera eyes, which provide them with image-forming vision. Vertebrate image-forming vision evolved independently from that of other animals and is regarded as a key innovation for enhancing predatory ability and ecological success. Evolutionary changes in the neural circuits, particularly the visual center, were central for the acquisition of image-forming vision. However, the evolutionary steps, from protochordates to jaw-less primitive vertebrates and then to jawed vertebrates, remain largely unknown. To bridge this gap, we present the detailed development of retinofugal projections in the lamprey, the neuroarchitecture in amphioxus, and the brain patterning in both animals. Both the lateral eye in larval lamprey and the frontal eye in amphioxus project to a light-detecting visual center in the caudal prosencephalic region marked by Pax6, which possibly represents the ancestral state of the chordate visual system. Our results indicate that the visual system of the larval lamprey represents an evolutionarily primitive state, forming a link from protochordates to vertebrates and providing a new perspective of brain evolution based on developmental mechanisms and neural functions. PMID:25233869

  19. Relationships between seasonal thermal variations and cell proliferation in heterothermic vertebrates, as revealed by PCNA expression in the brain of adult Rana bergeri (Günther, 1986).

    PubMed

    Margotta, Vito

    2012-01-01

    The cyclic variations of temperature with seasons, which are accompanied by variations in photoperiod, can activate proliferation in stem cells which survive in various organs and tissues of adult vertebrates, both poikilo- (aquatic and terrestrial) and homeothermic (male songbirds and Mammals). In the brain of these organisms such stem cells are mainly placed in the ependymal and/or sub-ependymal layers. To assess the influence of environmental temperature on the proliferative activity of those cells, an immunocytochemical investigation has been carried out on the brain of normal adult Rana bergeri, taken from the wild in late autumn and immediately submitted to observation. The results were compared with those of previous investigations on the same animal species, caught in their habitat in late autumn as in this study, but housed in standard laboratory environment for several days before beginning the experiments. I have now observed a widespread reduction in proliferation. This finding discordance is reasonably imputable to the former stay of the specimens in a thermostable environment during the previous investigations and appears in agreement with what is known from the literature for comparable experimental conditions, suggesting that a stay for days in a thermally stable, warm environment can counteract the anti-proliferative effect of exposition to the late autumn climate.

  20. Metabolomic Profiling of Post-Mortem Brain Reveals Changes in Amino Acid and Glucose Metabolism in Mental Illness Compared with Controls

    PubMed Central

    Zhang, Rong; Zhang, Tong; Ali, Ali Muhsen; Al Washih, Mohammed; Pickard, Benjamin; Watson, David G.

    2016-01-01

    Metabolomic profiling was carried out on 53 post-mortem brain samples from subjects diagnosed with schizophrenia, depression, bipolar disorder (SDB), diabetes, and controls. Chromatography on a ZICpHILIC column was used with detection by Orbitrap mass spectrometry. Data extraction was carried out with m/z Mine 2.14 with metabolite searching against an in-house database. There was no clear discrimination between the controls and the SDB samples on the basis of a principal components analysis (PCA) model of 755 identified or putatively identified metabolites. Orthogonal partial least square discriminant analysis (OPLSDA) produced clear separation between 17 of the controls and 19 of the SDB samples (R2CUM 0.976, Q2 0.671, p-value of the cross-validated ANOVA score 0.0024). The most important metabolites producing discrimination were the lipophilic amino acids leucine/isoleucine, proline, methionine, phenylalanine, and tyrosine; the neurotransmitters GABA and NAAG and sugar metabolites sorbitol, gluconic acid, xylitol, ribitol, arabinotol, and erythritol. Eight samples from diabetic brains were analysed, six of which grouped with the SDB samples without compromising the model (R2 CUM 0.850, Q2 CUM 0.534, p-value for cross-validated ANOVA score 0.00087). There appears on the basis of this small sample set to be some commonality between metabolic perturbations resulting from diabetes and from SDB. PMID:27076878

  1. The Unexpected Past of a Dwarf Galaxy

    NASA Astrophysics Data System (ADS)

    1996-08-01

    New Light on Cannibalism in the Local Group of Galaxies The Local Group of Galaxies consists of a few large spiral galaxies - for instance the Milky Way galaxy in which we live, and the Andromeda galaxy that is visible to the unaided eye in the northern constellation of the same name - as well as two dozen much smaller galaxies of mostly irregular shape. Whereas the larger galaxies have extended halos of very old stars, no such halos have ever been seen around the smaller ones. Now, however, Dante Minniti and Albert Zijlstra [1], working at the ESO 3.5-metre New Technology Telescope (NTT), have found a large halo of old and metal-poor stars around one of the dwarf galaxies in the Local Group. This finding is quite unexpected. It revises our understanding of star formation in these galaxies and provides important information about the past evolution of galaxies [2]. Galaxy halos The Milky Way galaxy is surrounded by a large, roughly spherical halo of old stars. The diameter is about 100,000 light years and the stars therein, known as Population II stars, are among the oldest known, with ages of 10 billion years or even more. They also differ from the younger stars nearer to the main plane of the Milky Way (in which our 4.7 billion year old Sun is located) by being very metal-poor. Many of the halo stars consist almost solely of hydrogen and helium, reflecting the composition of matter in the young Universe. This halo is important for our understanding of the processes that led to the formation of the Milky Way galaxy. It is believed that many of the halo stars and those of the same type found in globular clusters existed already before the Milky Way had fully formed. Galaxy cannibalism Many astronomers suspect that galaxies evolve and gradually grow larger and heavier by practising cannibalism on their own kind. In this picture, when two galaxies collide in space, the stars and nebulae in the smaller one will disperse and soon be taken over by the larger one, which

  2. Rescue of cytochrome P450 oxidoreductase (Por) mouse mutants reveals functions in vasculogenesis, brain and limb patterning linked to retinoic acid homeostasis.

    PubMed

    Ribes, Vanessa; Otto, Diana M E; Dickmann, Leslie; Schmidt, Katy; Schuhbaur, Brigitte; Henderson, Colin; Blomhoff, Rune; Wolf, C Roland; Tickle, Cheryll; Dollé, Pascal

    2007-03-01

    Cytochrome P450 oxidoreductase (POR) acts as an electron donor for all cytochrome P450 enzymes. Knockout mouse Por(-/-) mutants, which are early embryonic (E9.5) lethal, have been found to have overall elevated retinoic acid (RA) levels, leading to the idea that POR early developmental function is mainly linked to the activity of the CYP26 RA-metabolizing enzymes (Otto et al., Mol. Cell. Biol. 23, 6103-6116). By crossing Por mutants with a RA-reporter lacZ transgene, we show that Por(-/-) embryos exhibit both elevated and ectopic RA signaling activity e.g. in cephalic and caudal tissues. Two strategies were used to functionally demonstrate that decreasing retinoid levels can reverse Por(-/-) phenotypic defects, (i) by culturing Por(-/-) embryos in defined serum-free medium, and (ii) by generating compound mutants defective in RA synthesis due to haploinsufficiency of the retinaldehyde dehydrogenase 2 (Raldh2) gene. Both approaches clearly improved the Por(-/-) early phenotype, the latter allowing mutants to be recovered up until E13.5. Abnormal brain patterning, with posteriorization of hindbrain cell fates and defective mid- and forebrain development and vascular defects were rescued in E9.5 Por(-/-) embryos. E13.5 Por(-/-); Raldh2(+/-) embryos exhibited abdominal/caudal and limb defects that strikingly phenocopy those of Cyp26a1(-/-) and Cyp26b1(-/-) mutants, respectively. Por(-/-); Raldh2(+/-) limb buds were truncated and proximalized and the anterior-posterior patterning system was not established. Thus, POR function is indispensable for the proper regulation of RA levels and tissue distribution not only during early embryonic development but also in later morphogenesis and molecular patterning of the brain, abdominal/caudal region and limbs. PMID:17126317

  3. Fluctuations in electrodermal activity reveal variations in single trial brain responses to painful laser stimuli--a fMRI/EEG study.

    PubMed

    Mobascher, A; Brinkmeyer, J; Warbrick, T; Musso, F; Wittsack, H J; Stoermer, R; Saleh, A; Schnitzler, A; Winterer, G

    2009-02-01

    Pain is a complex experience with sensory, emotional and cognitive aspects. It also includes a sympathetic response that can be captured by measuring the electrodermal activity (EDA). The present study was performed to investigate which brain areas are associated with sympathetic activation in experimental pain; an issue that has not been addressed with fMRI (functional magnetic resonance imaging) thus far. Twelve healthy subjects received painful laser stimulation to the left hand. The event-related fMRI BOLD (blood oxygen level dependent) response was measured together with simultaneous EEG (electroencephalography) and EDA recordings. Laser stimuli induced the expected EDA response, evoked EEG potentials and BOLD responses. Single trial EDA amplitudes were used to guide further analysis of fMRI and EEG data. We found significantly higher BOLD responses in trials with high EDA vs. low EDA trials, predominantly in the insula and somatosensory cortex (S1/S2). Likewise, in the EEG we found the N2 laser evoked potentials to have significantly higher amplitudes in trials with high vs. low EDA. Furthermore EDA-informed BOLD modeling explained additional signal variance in sensory areas and yielded higher group level activation. We conclude that the sympathetic response to pain is associated with activation in pain-processing brain regions, predominantly in sensory areas and that single trial (EDA)-information can add to BOLD modeling by taking some of the response variability across trials and subjects into account. Thus, EDA is a useful additional, objective index when pain is studied with fMRI/EEG which might be of particular relevance in the context of genetic- and pharmacoimaging. PMID:18848631

  4. Newborn brain event-related potentials revealing atypical processing of sound frequency and the subsequent association with later literacy skills in children with familial dyslexia.

    PubMed

    Leppänen, Paavo H T; Hämäläinen, Jarmo A; Salminen, Hanne K; Eklund, Kenneth M; Guttorm, Tomi K; Lohvansuu, Kaisa; Puolakanaho, Anne; Lyytinen, Heikki

    2010-01-01

    The role played by an auditory-processing deficit in dyslexia has been debated for several decades. In a longitudinal study using brain event-related potentials (ERPs) we investigated 1) whether dyslexic children with familial risk background would show atypical pitch processing from birth and 2) how these newborn ERPs later relate to these same children's pre-reading cognitive skills and literacy outcomes. Auditory ERPs were measured at birth for tones varying in pitch and presented in an oddball paradigm (1100 Hz, 12%, and 1000 Hz, 88%). The brain responses of the typically reading control group children (TRC group, N=25) showed clear differentiation between the frequencies, while those of the group of reading disability with familial risk (RDFR, 8 children) and the group of typical readers with familial risk (TRFR, 14 children) did not differentiate between the tones. The ERPs of the latter two groups differed from those of the TRC group. However, the two risk groups also showed a differential hemispheric ERP pattern. Furthermore, newborn ERPs reflecting passive change detection were associated with phonological skills and letter knowledge prior to school age and with phoneme duration perception, reading speed (RS) and spelling accuracy in the 2nd grade of school. The early obligatory response was associated with more general pre-school language skills, as well as with RS and reading accuracy (RA). Results suggest that a proportion of dyslexic readers with familial risk background are affected by atypical auditory processing. This is already present at birth and also relates to pre-reading phonological processing and speech perception. These early differences in auditory processing could later affect phonological representations and reading development. However, atypical auditory processing is unlikely to suffice as a sole explanation for dyslexia but rather as one risk factor, dependent on the genetic profile of the child. PMID:20656284

  5. Transcriptome-wide mega-analyses reveal joint dysregulation of immunologic genes and transcription regulators in brain and blood in schizophrenia.

    PubMed

    Hess, Jonathan L; Tylee, Daniel S; Barve, Rahul; de Jong, Simone; Ophoff, Roel A; Kumarasinghe, Nishantha; Tooney, Paul; Schall, Ulrich; Gardiner, Erin; Beveridge, Natalie Jane; Scott, Rodney J; Yasawardene, Surangi; Perera, Antionette; Mendis, Jayan; Carr, Vaughan; Kelly, Brian; Cairns, Murray; Tsuang, Ming T; Glatt, Stephen J

    2016-10-01

    The application of microarray technology in schizophrenia research was heralded as paradigm-shifting, as it allowed for high-throughput assessment of cell and tissue function. This technology was widely adopted, initially in studies of postmortem brain tissue, and later in studies of peripheral blood. The collective body of schizophrenia microarray literature contains apparent inconsistencies between studies, with failures to replicate top hits, in part due to small sample sizes, cohort-specific effects, differences in array types, and other confounders. In an attempt to summarize existing studies of schizophrenia cases and non-related comparison subjects, we performed two mega-analyses of a combined set of microarray data from postmortem prefrontal cortices (n=315) and from ex-vivo blood tissues (n=578). We adjusted regression models per gene to remove non-significant covariates, providing best-estimates of transcripts dysregulated in schizophrenia. We also examined dysregulation of functionally related gene sets and gene co-expression modules, and assessed enrichment of cell types and genetic risk factors. The identities of the most significantly dysregulated genes were largely distinct for each tissue, but the findings indicated common emergent biological functions (e.g. immunity) and regulatory factors (e.g., predicted targets of transcription factors and miRNA species across tissues). Our network-based analyses converged upon similar patterns of heightened innate immune gene expression in both brain and blood in schizophrenia. We also constructed generalizable machine-learning classifiers using the blood-based microarray data. Our study provides an informative atlas for future pathophysiologic and biomarker studies of schizophrenia.

  6. Transcriptome-wide mega-analyses reveal joint dysregulation of immunologic genes and transcription regulators in brain and blood in schizophrenia.

    PubMed

    Hess, Jonathan L; Tylee, Daniel S; Barve, Rahul; de Jong, Simone; Ophoff, Roel A; Kumarasinghe, Nishantha; Tooney, Paul; Schall, Ulrich; Gardiner, Erin; Beveridge, Natalie Jane; Scott, Rodney J; Yasawardene, Surangi; Perera, Antionette; Mendis, Jayan; Carr, Vaughan; Kelly, Brian; Cairns, Murray; Tsuang, Ming T; Glatt, Stephen J

    2016-10-01

    The application of microarray technology in schizophrenia research was heralded as paradigm-shifting, as it allowed for high-throughput assessment of cell and tissue function. This technology was widely adopted, initially in studies of postmortem brain tissue, and later in studies of peripheral blood. The collective body of schizophrenia microarray literature contains apparent inconsistencies between studies, with failures to replicate top hits, in part due to small sample sizes, cohort-specific effects, differences in array types, and other confounders. In an attempt to summarize existing studies of schizophrenia cases and non-related comparison subjects, we performed two mega-analyses of a combined set of microarray data from postmortem prefrontal cortices (n=315) and from ex-vivo blood tissues (n=578). We adjusted regression models per gene to remove non-significant covariates, providing best-estimates of transcripts dysregulated in schizophrenia. We also examined dysregulation of functionally related gene sets and gene co-expression modules, and assessed enrichment of cell types and genetic risk factors. The identities of the most significantly dysregulated genes were largely distinct for each tissue, but the findings indicated common emergent biological functions (e.g. immunity) and regulatory factors (e.g., predicted targets of transcription factors and miRNA species across tissues). Our network-based analyses converged upon similar patterns of heightened innate immune gene expression in both brain and blood in schizophrenia. We also constructed generalizable machine-learning classifiers using the blood-based microarray data. Our study provides an informative atlas for future pathophysiologic and biomarker studies of schizophrenia. PMID:27450777

  7. The Unexpected Past of a Dwarf Galaxy

    NASA Astrophysics Data System (ADS)

    1996-08-01

    New Light on Cannibalism in the Local Group of Galaxies The Local Group of Galaxies consists of a few large spiral galaxies - for instance the Milky Way galaxy in which we live, and the Andromeda galaxy that is visible to the unaided eye in the northern constellation of the same name - as well as two dozen much smaller galaxies of mostly irregular shape. Whereas the larger galaxies have extended halos of very old stars, no such halos have ever been seen around the smaller ones. Now, however, Dante Minniti and Albert Zijlstra [1], working at the ESO 3.5-metre New Technology Telescope (NTT), have found a large halo of old and metal-poor stars around one of the dwarf galaxies in the Local Group. This finding is quite unexpected. It revises our understanding of star formation in these galaxies and provides important information about the past evolution of galaxies [2]. Galaxy halos The Milky Way galaxy is surrounded by a large, roughly spherical halo of old stars. The diameter is about 100,000 light years and the stars therein, known as Population II stars, are among the oldest known, with ages of 10 billion years or even more. They also differ from the younger stars nearer to the main plane of the Milky Way (in which our 4.7 billion year old Sun is located) by being very metal-poor. Many of the halo stars consist almost solely of hydrogen and helium, reflecting the composition of matter in the young Universe. This halo is important for our understanding of the processes that led to the formation of the Milky Way galaxy. It is believed that many of the halo stars and those of the same type found in globular clusters existed already before the Milky Way had fully formed. Galaxy cannibalism Many astronomers suspect that galaxies evolve and gradually grow larger and heavier by practising cannibalism on their own kind. In this picture, when two galaxies collide in space, the stars and nebulae in the smaller one will disperse and soon be taken over by the larger one, which

  8. Brains studying brains: look before you think in vision

    NASA Astrophysics Data System (ADS)

    Zhaoping, Li

    2016-06-01

    Using our own brains to study our brains is extraordinary. For example, in vision this makes us naturally blind to our own blindness, since our impression of seeing our world clearly is consistent with our ignorance of what we do not see. Our brain employs its ‘conscious’ part to reason and make logical deductions using familiar rules and past experience. However, human vision employs many ‘subconscious’ brain parts that follow rules alien to our intuition. Our blindness to our unknown unknowns and our presumptive intuitions easily lead us astray in asking and formulating theoretical questions, as witnessed in many unexpected and counter-intuitive difficulties and failures encountered by generations of scientists. We should therefore pay a more than usual amount of attention and respect to experimental data when studying our brain. I show that this can be productive by reviewing two vision theories that have provided testable predictions and surprising insights.

  9. An unexpectedly progressed lumbar herniated disk.

    PubMed

    Lipton, James A; McLeod, Geoffrey A

    2013-12-01

    The authors describe a case of a 26-year-old female military veteran who presented with low back pain that she attributed to a recent foot injury. The patient reported a history of lumbar pain while in the military that had been treated successfully with high-velocity, low-amplitude osteopathic manipulative treatment. The patient's current pain was improved with osteopathic manipulative treatment and gait correction. Several weeks after her initial presentation, the patient reported that she had had a herniated disk diagnosed 2 years earlier by means of magnetic resonance imaging. Updated magnetic resonance imaging was performed, the results of which revealed a large herniated disk that had caused severe stenosis. The patient was immediately referred to a neurosurgeon for consultation and subsequently underwent surgical treatment. PMID:24285036

  10. Vigilance Task-Related Change in Brain Functional Connectivity as Revealed by Wavelet Phase Coherence Analysis of Near-Infrared Spectroscopy Signals

    PubMed Central

    Wang, Wei; Wang, Bitian; Bu, Lingguo; Xu, Liwei; Li, Zengyong; Fan, Yubo

    2016-01-01

    This study aims to assess the vigilance task-related change in connectivity in healthy adults using wavelet phase coherence (WPCO) analysis of near-infrared spectroscopy signals (NIRS). NIRS is a non-invasive neuroimaging technique for assessing brain activity. Continuous recordings of the NIRS signals were obtained from the prefrontal cortex (PFC) and sensorimotor cortical areas of 20 young healthy adults (24.9 ± 3.3 years) during a 10-min resting state and a 20-min vigilance task state. The vigilance task was used to simulate driving mental load by judging three random numbers (i.e., whether odd numbers). The task was divided into two sessions: the first 10 min (Task t1) and the second 10 min (Task t2). The WPCO of six channel pairs were calculated in five frequency intervals: 0.6–2 Hz (I), 0.145–0.6 Hz (II), 0.052–0.145 Hz (III), 0.021–0.052 Hz (IV), and 0.0095–0.021 Hz (V). The significant WPCO formed global connectivity (GC) maps in intervals I and II and functional connectivity (FC) maps in intervals III to V. Results show that the GC levels in interval I and FC levels in interval III were significantly lower in the Task t2 than in the resting state (p < 0.05), particularly between the left PFC and bilateral sensorimotor regions. Also, the reaction time (RT) shows an increase in Task t2 compared with that in Task t1. However, no significant difference in WPCO was found between Task t1 and resting state. The results showed that the change in FC at the range of 0.6–2 Hz was not attributed to the vigilance task per se, but the interaction effect of vigilance task and time factors. The findings suggest that the decreased attention level might be partly attributed to the reduced GC levels between the left prefrontal region and sensorimotor area. The present results provide a new insight into the vigilance task-related brain activity. PMID:27547182

  11. Vigilance Task-Related Change in Brain Functional Connectivity as Revealed by Wavelet Phase Coherence Analysis of Near-Infrared Spectroscopy Signals.

    PubMed

    Wang, Wei; Wang, Bitian; Bu, Lingguo; Xu, Liwei; Li, Zengyong; Fan, Yubo

    2016-01-01

    This study aims to assess the vigilance task-related change in connectivity in healthy adults using wavelet phase coherence (WPCO) analysis of near-infrared spectroscopy signals (NIRS). NIRS is a non-invasive neuroimaging technique for assessing brain activity. Continuous recordings of the NIRS signals were obtained from the prefrontal cortex (PFC) and sensorimotor cortical areas of 20 young healthy adults (24.9 ± 3.3 years) during a 10-min resting state and a 20-min vigilance task state. The vigilance task was used to simulate driving mental load by judging three random numbers (i.e., whether odd numbers). The task was divided into two sessions: the first 10 min (Task t1) and the second 10 min (Task t2). The WPCO of six channel pairs were calculated in five frequency intervals: 0.6-2 Hz (I), 0.145-0.6 Hz (II), 0.052-0.145 Hz (III), 0.021-0.052 Hz (IV), and 0.0095-0.021 Hz (V). The significant WPCO formed global connectivity (GC) maps in intervals I and II and functional connectivity (FC) maps in intervals III to V. Results show that the GC levels in interval I and FC levels in interval III were significantly lower in the Task t2 than in the resting state (p < 0.05), particularly between the left PFC and bilateral sensorimotor regions. Also, the reaction time (RT) shows an increase in Task t2 compared with that in Task t1. However, no significant difference in WPCO was found between Task t1 and resting state. The results showed that the change in FC at the range of 0.6-2 Hz was not attributed to the vigilance task per se, but the interaction effect of vigilance task and time factors. The findings suggest that the decreased attention level might be partly attributed to the reduced GC levels between the left prefrontal region and sensorimotor area. The present results provide a new insight into the vigilance task-related brain activity. PMID:27547182

  12. On the Independent Origins of Complex Brains and Neurons

    PubMed Central

    Moroz, Leonid L.

    2009-01-01

    Analysis of the origin and evolution of neurons is crucial for revealing principles of organization of neural circuits with unexpected implications for genomic sciences, biomedical applications and regenerative medicine. This article presents an overview of some controversial ideas about the origin and evolution of neurons and nervous systems, focusing on the independent origin of complex brains and possible independent origins of neurons. First, earlier hypotheses related to the origin of neurons are summarized. Second, the diversity of nervous systems and convergent evolution of complex brains in relation to current views about animal phylogeny is discussed. Third, the lineages of molluscs and basal metazoans are used as illustrated examples of multiple origins of complex brains and neurons. Finally, a hypothesis about the independent origin of complex brains, centralized nervous systems and neurons is outlined. Injury-associated mechanisms leading to secretion of signal peptides (and related molecules) can be considered as evolutionary predecessors of inter-neuronal signaling and the major factors in the appearance of neurons in the first place. PMID:20029182

  13. Acute mesenteric ischaemia and unexpected death.

    PubMed

    Byard, Roger W

    2012-05-01

    Acute mesenteric ischaemia is a vascular emergency that arises when blood flow to the intestine is compromised leading to tissue necrosis. It is primarily a condition of the elderly associated with significant morbidity and mortality. Causes include arterial thromboembolism, venous thrombosis and splanchnic vasoconstriction (so-called nonocclusive mesenteric ischaemia). Reperfusion injury and breakdown of the intestinal mucosal barrier lead to metabolic derangements, sepsis and death from multiorgan failure. The diagnosis may be difficult to make clinically and numbers of cases are increasing due to ageing of the population. The clinical and pathological features are reviewed with discussion of predisposing conditions. Careful dissection of the mesenteric vasculature is required at autopsy with appropriate histologic sampling and documentation of associated comorbidities. Other organs need to be checked for thrombi and the possibility of testing for inherited thombophilias should be considered. Toxicological evaluation, particularly in younger individuals, may reveal evidence of cocaine use. On occasion no obstructive lesions will be demonstrated, however the confounding effects of post-mortem autolytic and putrefactive changes may mean that nonocclusive mesenteric ischaemia may be difficult to diagnose.

  14. The thermal properties of beeswaxes: unexpected findings.

    PubMed

    Buchwald, Robert; Breed, Michael D; Greenberg, Alan R

    2008-01-01

    Standard melting point analyses only partially describe the thermal properties of eusocial beeswaxes. Differential scanning calorimetry (DSC) revealed that thermal phase changes in wax are initiated at substantially lower temperatures than visually observed melting points. Instead of a sharp, single endothermic peak at the published melting point of 64 degrees C, DSC analysis of Apis mellifera Linnaeus wax yielded a broad melting curve that showed the initiation of melting at approximately 40 degrees C. Although Apis beeswax retained a solid appearance at these temperatures, heat absorption and initiation of melting could affect the structural characteristics of the wax. Additionally, a more complete characterization of the thermal properties indicated that the onset of melting, melting range and heat of fusion of beeswaxes varied significantly among tribes of social bees (Bombini, Meliponini, Apini). Compared with other waxes examined, the relatively malleable wax of bumblebees (Bombini) had the lowest onset of melting and lowest heat of fusion but an intermediate melting temperature range. Stingless bee (Meliponini) wax was intermediate between bumblebee and honeybee wax (Apini) in heat of fusion, but had the highest onset of melting and the narrowest melting temperature range. The broad melting temperature range and high heat of fusion in the Apini may be associated with the use of wax comb as a free-hanging structural material, while the Bombini and Meliponini support their wax structures with exogenous materials.

  15. The ATP-binding site of brain phosphatidylinositol 4-kinase PI4K230 as revealed by 5'-p-fluorosulfonylbenzoyladenosine.

    PubMed

    Vereb, G; Balla, A; Gergely, P; Wymann, M P; Gülkan, H; Suer, S; Heilmeyer, L M

    2001-03-01

    The ATP-binding site of purified bovine brain phosphatidylinositol 4-kinase 230 (PI4K230) was studied by its reaction with 5'-p-fluorosulfonylbenzoyladenosine (FSBA), an ATP-like alkylating reagent. Four hundred to eight hundred micromolar FSBA inactivated PI4K230 specifically with apparently first-order kinetics and resulted in 50% loss of enzyme activity in 36--130 min. The specificity of the reaction with FSBA was demonstrated by the lack of inactivation with 5'-p-fluorosulfonylbenzoyl chloride and by protection with ATP and ATP analogues against inactivation. Most ATP analogues competed with FSBA inactivation in order of their increasing hydrophobicity, parallel to their inhibitory potency in activity measurements. The specific binding of FSBA to PI4K230 was demonstrated also by Western-blot experiments. These results suggest that FSBA-reactive group(s) involved in the enzyme activity are located near to the ATP-binding site in a hydrophobic region of native PI4K230. Experiments with site-directed mutagenesis indicate that the conserved Lys-1792 plays essential role in the enzyme activity and serves as one target of affinity labelling by FSBA. Prevention of both Lys-1792-directed and Lys-1792-independent binding of FSBA by Cibacron Blue 3GA suggest that these sites are located spatially close to each other. PMID:11311856

  16. An unexpected twist in viral capsid maturation

    SciTech Connect

    Gertsman, Ilya; Gan, Lu; Guttman, Miklos; Lee, Kelly; Speir, Jeffrey A.; Duda, Robert L.; Hendrix, Roger W.; Komives, Elizabeth A.; Johnson, John E.

    2009-04-14

    Lambda-like double-stranded (ds) DNA bacteriophage undergo massive conformational changes in their capsid shell during the packaging of their viral genomes. Capsid shells are complex organizations of hundreds of protein subunits that assemble into intricate quaternary complexes that ultimately are able to withstand over 50 atm of pressure during genome packaging. The extensive integration between subunits in capsids requires the formation of an intermediate complex, termed a procapsid, from which individual subunits can undergo the necessary refolding and structural rearrangements needed to transition to the more stable capsid. Although various mature capsids have been characterized at atomic resolution, no such procapsid structure is available for a dsDNA virus or bacteriophage. Here we present a procapsid X-ray structure at 3.65 {angstrom} resolution, termed prohead II, of the lambda-like bacteriophage HK97, the mature capsid structure of which was previously solved to 3.44 {angstrom}. A comparison of the two largely different capsid forms has unveiled an unprecedented expansion mechanism that describes the transition. Crystallographic and hydrogen/deuterium exchange data presented here demonstrate that the subunit tertiary structures are significantly different between the two states, with twisting and bending motions occurring in both helical and -sheet regions. We also identified subunit interactions at each three-fold axis of the capsid that are maintained throughout maturation. The interactions sustain capsid integrity during subunit refolding and provide a fixed hinge from which subunits undergo rotational and translational motions during maturation. Previously published calorimetric data of a closely related bacteriophage, P22, showed that capsid maturation was an exothermic process that resulted in a release of 90 kJ mol{sup -1} of energy. We propose that the major tertiary changes presented in this study reveal a structural basis for an exothermic

  17. Brain herniation

    MedlinePlus

    ... herniation; Uncal herniation; Subfalcine herniation; Tonsillar herniation; Herniation - brain ... Brain herniation occurs when something inside the skull produces pressure that moves brain tissues. This is most ...

  18. Flow cytometry analysis of synaptosomes from post-mortem human brain reveals changes specific to Lewy Body and Alzheimer’s Disease

    PubMed Central

    Postupna, Nadia O.; Keene, C. Dirk; Latimer, Caitlin; Sherfield, Emily E.; Van Gelder, Rachel D.; Ojemann, Jeffrey G.; Montine, Thomas J.; Darvas, Martin

    2014-01-01

    Synaptic dysfunction is thought to play an important role in the pathophysiology of neurodegenerative diseases, such as Alzheimer’s disease (AD) and Lewy body disease (LBD). To improve our understanding of synaptic alterations in health and disease, we investigated synaptosomes prepared from post-mortem human cerebral cortex, putamen, and two regions of the caudate nucleus, dorso-lateral (DL) and ventro-medial (VM), regions commonly affected in AD and LBD. We observed that the fraction of synaptosomal particles with reactivity for dopamine transporter (DAT) was significantly reduced in the putamen and VM caudate of patients with neuropathological diagnosis of LBD. As expected, these differences also were reflected in direct measurements of dopamine (DA) and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), in caudate and putamen of LBD patients. The fraction of synaptosomal particles positive for amyloid β (Aβ) was significantly increased in frontal cortical samples of patients with the neuropathological diagnosis of severe AD, and was positively correlated with disease progression. We also prepared synaptosomes from the striatum of mice with severe loss of DA neurons (Slc6a3-DTR mice) and wild-type littermate controls. We observed dramatically reduced levels of DAT-positive synaptosomes in Slc6a3-DTR mice following exposure to diphtheria toxin (DT). Striatal levels of DA and DOPAC in Slc6a3-DTR mice also were reduced significantly following DT exposure. We conclude that flow cytometric analysis of synaptosomes prepared from human or mouse brain provides an opportunity to study expression of pathology-associated proteins and also the specific loss of dopaminergic nerve terminals. Hence, we believe it is a valid method to detect pathological changes at the level of the synapse in LBD as well as AD. PMID:25068655

  19. Sudden unexpected death due to strangulated inguinal hernia.

    PubMed

    Menezes, Ritesh G; Padubidri, Jagadish Rao; Raghavendra Babu, Y P; Naik, Ramadas; Kanchan, Tanuj; Senthilkumaran, Subramanian; Chawla, Khushboo

    2016-06-01

    Sudden unwitnessed, unexpected deaths when the bodies are found in public places require a complete and meticulous medicolegal autopsy to ascertain the cause and manner of death to avoid further unnecessary investigations by the legal authorities. Such deaths attributed to gastrointestinal causes at autopsy are relatively uncommon. We report a case of sudden unexpected death due to strangulated inguinal hernia in a 60-year-old man. The body was discovered in a public area near a place of worship. The present case illustrates a potentially preventable sudden unexpected death due to a surgically correctable gastrointestinal condition. In the present case, the individual feared being hospitalised for treatment of his scrotal swelling with potential surgery and the eventual loss of daily income. In our opinion, such apprehensions may have delayed the potentially life-saving hospital surgical intervention in the individual. PMID:26837567

  20. Expected versus unexpected panic attacks: a naturalistic prospective study.

    PubMed

    Kenardy, J; Taylor, C B

    1999-01-01

    The purpose of this study was to identify factors that are associated with expectation of panic attacks as well as to validate the hypothesized tendency to identify false (panic) alarms in panic disorder. Ten women with panic disorder were assessed naturalistically using computer-assisted self-monitoring. This allowed for prospective assessment of expected versus unexpected panic attacks. Expectation of panic attacks was associated with panic occurrence, as well as elevated sense of threat or danger, anxiety, helplessness, avoidance, distress about physical symptoms, physical sensations, and catastrophic thoughts prior to the attack. In general, the state measured prior to unexpected attacks did not differ from ongoing nonpanic state. Furthermore, none of the variables measured during the attacks were able to distinguish unexpected attacks from expected attacks.