| 1. |
- El-Sayed, Najib M., et al.
(författare)
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The genome sequence of Trypanosoma cruzi, etiologic agent of Chagas disease.
- 2005
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 309:5733, s. 409-15
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Tidskriftsartikel (refereegranskat)abstract
- Whole-genome sequencing of the protozoan pathogen Trypanosoma cruzi revealed that the diploid genome contains a predicted 22,570 proteins encoded by genes, of which 12,570 represent allelic pairs. Over 50% of the genome consists of repeated sequences, such as retrotransposons and genes for large families of surface molecules, which include trans-sialidases, mucins, gp63s, and a large novel family (>1300 copies) of mucin-associated surface protein (MASP) genes. Analyses of the T. cruzi, T. brucei, and Leishmania major (Tritryp) genomes imply differences from other eukaryotes in DNA repair and initiation of replication and reflect their unusual mitochondrial DNA. Although the Tritryp lack several classes of signaling molecules, their kinomes contain a large and diverse set of protein kinases and phosphatases; their size and diversity imply previously unknown interactions and regulatory processes, which may be targets for intervention.
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| 2. |
- Wallén-Mackenzie, Åsa, et al.
(författare)
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Restricted cortical and amygdaloid removal of vesicular glutamate transporter 2 in preadolescent mice impacts dopaminergic activity and neuronal circuitry of higher brain function.
- 2009
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Ingår i: The Journal of neuroscience : the official journal of the Society for Neuroscience. - 1529-2401 .- 0270-6474. ; 29:7, s. 2238-51
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Tidskriftsartikel (refereegranskat)abstract
- A major challenge in neuroscience is to resolve the connection between gene functionality, neuronal circuits, and behavior. Most, if not all, neuronal circuits of the adult brain contain a glutamatergic component, the nature of which has been difficult to assess because of the vast cellular abundance of glutamate. In this study, we wanted to determine the role of a restricted subpopulation of glutamatergic neurons within the forebrain, the Vglut2-expressing neurons, in neuronal circuitry of higher brain function. Vglut2 expression was selectively deleted in the cortex, hippocampus, and amygdala of preadolescent mice, which resulted in increased locomotor activity, altered social dominance and risk assessment, decreased sensorimotor gating, and impaired long-term spatial memory. Presynaptic VGLUT2-positive terminals were lost in the cortex, striatum, nucleus accumbens, and hippocampus, and a downstream effect on dopamine binding site availability in the striatum was evident. A connection between the induced late-onset, chronic reduction of glutamatergic neurotransmission and dopamine signaling within the circuitry was further substantiated by a partial attenuation of the deficits in sensorimotor gating by the dopamine-stabilizing antipsychotic drug aripiprazole and an increased sensitivity to amphetamine. Somewhat surprisingly, given the restricted expression of Vglut2 in regions responsible for higher brain function, our analyses show that VGLUT2-mediated neurotransmission is required for certain aspects of cognitive, emotional, and social behavior. The present study provides support for the existence of a neurocircuitry that connects changes in VGLUT2-mediated neurotransmission to alterations in the dopaminergic system with schizophrenia-like behavioral deficits as a major outcome.
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| 3. |
- Andersson, Daniel C
(författare)
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Mitochondria, contractility and Ca2+ handling : cardiac and skeletal muscle adaptations in health and disease
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Contractility is a fundamental feature of skeletal and cardiac muscles. An indispensable step in the cellular signal for contraction is a transient elevation in cytoplasmic free [Ca2+] ([Ca2+]i). Both the production of contractile force and Ca2+ handling processes are highly energy demanding. Mitochondrial ATP production from the respiratory chain is thus of pivotal importance for muscle cell function. Moreover, the mitochondria are also directly involved in Ca2+ signaling and are the foremost source of reactive oxygen species (ROS). Mutations in the genomes encoding for the mitochondrial respiratory chain, either the nuclear or the mitochondrial (mtDNA) genome, can give rise to primary mitochondrial diseases. Mitochondrial dysfunction is also implicated in other diseases, such as heart failure, obesity and diabetes. Paper I and II investigate two mouse models of primary mitochondrial myopathy (Tfam KO) and cardiomyopathy (Mterf3 KO). Furthermore, the obese, pre-diabetic ob/ob mouse was studied in papers III and IV. Skeletal and cardiac muscle cells were studied primarily with respect to contractility, [Ca2+]i and mitochondrial ROS production. Skeletal muscle fibers of myopathy Tfam KO mice produce less force compared to control mice. This was explained by reduced tetanic [Ca2+]i, decreased SR Ca2+ release and reduced SR Ca2+ storage via calsequestrin 2. Moreover, Tfam KO but not control fibers, displayed a markedly increased mitochondrial [Ca2+] during fatigue, partly through a cyclosporin A-sensitive mechanism. Elevated [Ca2+] in the mitochondria can trigger cellular damage. Thus, reducing mitochondrial Ca2+ with cyclosporin A may provide one way for treatment of mitochondrial myopathy. Mterf3 KO mice develop hypertrophic cardiomyopathy and die suddenly. Cardiomyocytes from these mice display elevated SR Ca2+ cycling, increased SR Ca2+ load and aberrant pro-arrhythmic Ca2+ releases compatible with that seen in sympathetic stimulation. In support of this, electrocardiography revealed signs of elevated catecholaminergic drive. Moreover, in the moribund stage Mterf3 KO mice develop terminal AV-block and bradycardia. Acutely exposing WT cardiomyocytes to an excess of the saturated fatty acid palmitate caused dissipation of the mitochondrial membrane potential and a large increase in mitochondrial ROS production. In turn, this ROS increase impaired the cellular Ca2+ cycling and contractility. However in ob/ob cardiomyocytes, palmitate did not cause increased ROS production and the function of ob/ob cardiomyocytes was in fact improved by palmitate. This suggests that the ob/ob heart has adapted to a high fat environment and metabolizes fatty acids without the producing large amounts of mitochondrial ROS. In WT cardiomyocytes, application of the beta-adrenergic agonist isoproterenol (ISO) stimulated mitochondrial ROS production. Concomitant application of the ROS scavenger N-acetylcysteine (NAC) diminished the inotropic effect of ISO on cardiomyocyte [Ca2+]i transients and contractility. On the other hand, ob/ob cardiomyocytes failed to increase ROS production when exposed to ISO and NAC did not alter the effect of ISO on [Ca2+]i transients. Hence, mitochondrial ROS is integrated in, but not essential to, the inotropic mechanism of beta-adrenergic stimulation. In all the studied disease models, neither an increase in mitochondrial ROS production nor signs of oxidative damage were found. In conclusion, dysfunctional mitochondria cause long-term adaptive/maladaptive changes in Ca2+ handling as seen in the Tfam and Mterf3 KO mice. Mitochondrial functions can influence cellular Ca2+ handling also in the short term. This is evident by the effects of palmitate and ISO-stimulated mitochondrial ROS production.
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| 4. |
- Li, Lizhen, 1977, et al.
(författare)
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Protective role of reactive astrocytes in brain ischemia.
- 2008
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Ingår i: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 28:3, s. 468-81
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Tidskriftsartikel (refereegranskat)abstract
- Reactive astrocytes are thought to protect the penumbra during brain ischemia, but direct evidence has been lacking due to the absence of suitable experimental models. Previously, we generated mice deficient in two intermediate filament (IF) proteins, glial fibrillary acidic protein (GFAP) and vimentin, whose upregulation is the hallmark of reactive astrocytes. GFAP(-/-)Vim(-/-) mice exhibit attenuated posttraumatic reactive gliosis, improved integration of neural grafts, and posttraumatic regeneration. Seven days after middle cerebral artery (MCA) transection, infarct volume was 210 to 350% higher in GFAP(-/-)Vim(-/-) than in wild-type (WT) mice; GFAP(-/-), Vim(-/-) and WT mice had the same infarct volume. Endothelin B receptor (ET(B)R) immunoreactivity was strong on cultured astrocytes and reactive astrocytes around infarct in WT mice but undetectable in GFAP(-/-)Vim(-/-) astrocytes. In WT astrocytes, ET(B)R colocalized extensively with bundles of IFs. GFAP(-/-)Vim(-/-) astrocytes showed attenuated endothelin-3-induced blockage of gap junctions. Total and glutamate transporter-1 (GLT-1)-mediated glutamate transport was lower in GFAP(-/-)Vim(-/-) than in WT mice. DNA array analysis and quantitative real-time PCR showed downregulation of plasminogen activator inhibitor-1 (PAI-1), an inhibitor of tissue plasminogen activator. Thus, reactive astrocytes have a protective role in brain ischemia, and the absence of astrocyte IFs is linked to changes in glutamate transport, ET(B)R-mediated control of gap junctions, and PAI-1 expression.
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| 5. |
- Tamas, Ivica, et al.
(författare)
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Endosymbiont gene functions impaired and rescued by polymerase infidelity at poly(A) tracts
- 2008
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 105:39, s. 14934-14939
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Tidskriftsartikel (refereegranskat)abstract
- Among host-dependent bacteria that have evolved by extreme reductive genome evolution, long-term bacterial endosymbionts of insects have the smallest (160-790 kb) and most A + T-rich (>70%) bacterial genomes known to date. These genomes are riddled with poly(A) tracts, and 5-50% of genes contain tracts of 10 As or more. Here, we demonstrate transcriptional slippage at poly(A) tracts within genes of Buchnera aphidicola associated with aphids and Blochmannia pennsylvanicus associated with ants. Several tracts contain single frameshift deletions; these apparent pseudogenes showed patterns of constraint consistent with purifying selection on the encoded proteins. Transcriptional slippage yielded a heterogeneous population of transcripts with variable numbers of As in the tract. Across several frameshifted genes, including B. aphidicola cell wall biosynthesis genes and a B. pennsylvanicus histidine biosynthesis gene, 12-50% of transcripts contained corrected reading frames that could potentially yield full-length proteins. In situ immunostaining confirmed the production of the cell wall biosynthetic enzyme UDP-N-acetylmuramyl pentapeptide synthase encoded by the frameshifted murF gene. Simulation studies indicated an overrepresentation of poly(A) tracts in endosymbiont genomes relative to other A + T-rich bacterial genomes. Polymerase infidelity at poly(A) tracts rescues the functionality of genes with frameshift mutations and, conversely, reduces the efficiency of expression for in-frame genes carrying poly(A) regions. These features of homopolymeric tracts could be exploited to manipulate gene expression in small synthetic genomes.
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