bluuebunny/crossref_metadata_2025 huggingface dataset:
Autonomic Denervation of Lymphoid Organs Leads to Epigenetic Immune Atrophy in a Mouse Model of Krabbe Disease
Authors: Galbiati Francesca , Basso Veronica , Cantuti Ludovico , Givogri Maria Irene , Lopez-Rosas Aurora , Perez Nicolas , Vasu Chenthamarakshan , Cao Hongmei , van Breemen Richard , Mondino Anna , Bongarzone Ernesto R.
Published: December 2007

Lysosomal β-galactosylceramidase deficiency results in demyelination and inflammation in the nervous system causing the neurological Krabbe disease. In theTwitchermouse model of this disease, we found that neurological symptoms parallel progressive and severe lymphopenia. Although lymphopoiesis is normal before disease onset, primary and secondary lymphoid organs progressively degenerate afterward. This occurs despite preserved erythropoiesis and leads to severe peripheral lymphopenia caused by reduced numbers of T cell precursors and mature lymphocytes. Hematopoietic cell replacement experiments support the existence of an epigenetic factor in mutant mice reconcilable with a progressive loss of autonomic axons that hampers thymic functionality. We propose that degeneration of autonomic nerves leads to the irreversible thymic atrophy and loss of immune-competence. Our study describes a new aspect of Krabbe disease, placing patients at risk of immune-related pathologies, and identifies a novel target for therapeutic interventions.
GluR1 Links Structural and Functional Plasticity at Excitatory Synapses
Authors: Kopec Charles D. , Real Eleonore , Kessels Helmut W. , Malinow Roberto
Published: December 2007

Long-term potentiation (LTP), a cellular model of learning and memory, produces both an enhancement of synaptic function and an increase in the size of the associated dendritic spine. Synaptic insertion of AMPA receptors is known to play an important role in mediating the increase in synaptic strength during LTP, whereas the role of AMPA receptor trafficking in structural changes remains unexplored. Here, we examine how the cell maintains the correlation between spine size and synapse strength during LTP. We found that cells exploit an elegant solution by linking both processes to a single molecule: the AMPA-type glutamate receptor subunit 1 (GluR1). Synaptic insertion of GluR1 is required to permit a stable increase in spine size, both in hippocampal slice cultures andin vivo. Synaptic insertion of GluR1 is not sufficient to drive structural plasticity. Although crucial to the expression of LTP, the ion channel function of GluR1 is not required for the LTP-driven spine size enhancement. Remarkably, a recombinant cytosolic C-terminal fragment (C-tail) of GluR1 is driven to the postsynaptic density after an LTP stimulus, and the synaptic incorporation of this isolated GluR1 C-tail is sufficient to permit spine enlargement even when postsynaptic exocytosis of endogenous GluR1 is blocked. We conclude that during plasticity, synaptic insertion of GluR1 has two functions: the established role of increasing synaptic strength via its ligand-gated ion channel, and a novel role through the structurally stabilizing effect of its C terminus that permits an increase in spine size.
cAMP Response Element-Binding Protein-Mediated Gene Expression Increases the Intrinsic Excitability of CA1 Pyramidal Neurons
Authors: Lopez de Armentia Mikel , Jancic Dragana , Olivares Roman , Alarcon Juan M. , Kandel Eric R. , Barco Angel
Published: December 2007

To investigate the role of CREB-mediated gene expression on the excitability of CA1 pyramidal neurons, we obtained intracellular recordings from pyramidal neurons of transgenic mice expressing a constitutively active form of CREB, VP16–CREB, in a regulated and restricted manner. We found that transgene expression increased the neuronal excitability and inhibited the slow and medium afterhyperpolarization currents. These changes may contribute to the reduced threshold for LTP observed in these mice. When strong transgene expression was turned on for prolonged period of time, these mice also showed a significant loss of hippocampal neurons and sporadic epileptic seizures. These deleterious effects were dose dependent and could be halted, but not reversed by turning off transgene expression. Our experiments reveal a new role for hippocampal CREB-mediated gene expression, identify the slow afterhyperpolarization as a primary target of CREB action, provide a new mouse model to investigate temporal lobe epilepsy and associated neurodegeneration, and illustrate the risks of cell death associated to a sustained manipulation of this pathway. As a result, our study has important implications for both the understanding of the cellular bases of learning and memory and the consideration of therapies targeted to the CREB pathway.
Vestibular Signals in Primate Thalamus: Properties and Origins
Authors: Meng Hui , May Paul J. , Dickman J. David , Angelaki Dora E.
Published: December 2007

Vestibular activation is found in diverse cortical areas. To characterize the pathways and types of signals supplied to cortex, we recorded responses to rotational and/or translational stimuli in the macaque thalamus. Few cells responded to rotation alone, with most showing convergence between semicircular canal and otolith signals. During sinusoidal rotation, thalamic responses lead head velocity by ∼30° on average at frequencies between 0.01–4 Hz. During translation, neurons encoded combinations of linear acceleration and velocity. In general, thalamic responses were similar to those recorded in the vestibular and cerebellar nuclei using identical testing paradigms, but differed from those of vestibular afferents. Thalamic responses represented a biased continuum: most cells more strongly encoded translation and fewer cells modulated primarily in response to net gravitoinertial acceleration. Responsive neurons were scattered within a large area that included regions of the ventral posterior and ventral lateral nuclei, and so were not restricted to the known vestibular nuclei projection zones. To determine the origins of these responses, a retrograde tracer was injected into a dorsolateral thalamic site where rotation/translation-sensitive cells were encountered. This injection labeled neurons in the rostral contralateral anterior interposed and fastigial nuclei, but did not label cells within the vestibular nuclei. Examination of thalamic terminations after tracer injections into the cerebellar and vestibular nuclei indicated that most vestibular responsive units fall within the thalamic terminal zones of these nuclei. Thus, vestibular signals, which are supplied to the thalamus from both vestibular and cerebellar nuclei, are positioned for distribution to widespread cortical areas.
Insulin Dysfunction InducesIn VivoTau Hyperphosphorylation through Distinct Mechanisms
Authors: Planel Emmanuel , Tatebayashi Yoshitaka , Miyasaka Tomohiro , Liu Li , Wang Lili , Herman Mathieu , Yu W. Haung , Luchsinger Jose A. , Wadzinski Brian , Duff Karen E. , Takashima Akihiko
Published: December 2007

Hyperphosphorylated tau is the major component of paired helical filaments in neurofibrillary tangles found in Alzheimer's disease (AD) brains, and tau hyperphosphorylation is thought to be a critical event in the pathogenesis of the disease. The large majority of AD cases is late onset and sporadic in origin, with aging as the most important risk factor. Insulin resistance, impaired glucose tolerance, and diabetes mellitus (DM) are other common syndromes in the elderly also strongly age dependent, and there is evidence supporting a link between insulin dysfunction and AD. To investigate the possibility that insulin dysfunction might promote tau pathology, we induced insulin deficiency and caused DM in mice with streptozotocin (STZ). A mild hyperphosphorylation of tau could be detected 10, 20, and 30 d after STZ injection, and a massive hyperphosphorylation of tau was observed after 40 d. The robust hyperphosphorylation of tau was localized in the axons and neuropil, and prevented tau binding to microtubules. Neither mild nor massive tau phosphorylation induced tau aggregation. Body temperature of the STZ-treated mice did not differ from control animals during 30 d, but dropped significantly thereafter. No change in β-amyloid (Aβ) precursor protein (APP), APP C-terminal fragments, or Aβ levels were observed in STZ-treated mice; however, cellular protein phosphatase 2A activity was significantly decreased. Together, these data indicate that insulin dysfunction induced abnormal tau hyperphosphorylation through two distinct mechanisms: one was consequent to hypothermia; the other was temperature-independent, inherent to insulin depletion, and probably caused by inhibition of phosphatase activity.
Target Cell-Specific Involvement of Presynaptic Mitochondria in Post-Tetanic Potentiation at Hippocampal Mossy Fiber Synapses
Authors: Lee Doyun , Lee Kyu-Hee , Ho Won-Kyung , Lee Suk-Ho
Published: December 2007

Previous studies indicate that boutons from the same axon exhibit distinct Ca2+dynamics depending on the postsynaptic targets. Mossy fibers of hippocampal granule cells innervate synaptic targets via morphologically distinct boutons. We investigated mitochondrial involvement in the generation of post-tetanic residual Ca2+(Cares) at large and smallen passantmossy fiber boutons (MFBs). Mitochondria limited the [Ca2+]ibuild-up during high-frequency stimulation (HFS) at large MFBs, but not at small MFBs. The amount of Cares, quantified as a time integral of residual [Ca2+]i, was significantly larger at large MFBs than at small MFBs, and that at large MFBs was substantially attenuated by inhibitors of mitochondrial Ca2+uniporter and mitochondrial Na+/Ca2+exchanger (mitoNCX). In contrast, blockers of mitoNCX had no effect on the Caresat small MFBs. Post-tetanic Careshas been proposed as a mechanism for post-tetanic potentiation (PTP). We examined mitochondrial involvement in PTP at mossy fiber synapses on hilar mossy cells (MF→MC synapse) and on hilar interneurons (MF→HI synapse), which are presumably innervated via large and small MFBs, respectively. Consistent with the differential contribution of mitochondria to Caresat large and small MFBs, mitoNCX blockers significantly reduced the PTP at the MF→MC synapse, but not at the MF→HI synapse. In contrast, protein kinase C (PKC) inhibitors significantly reduced the PTP at MF→HI synapse, but not at the MF→MC synapse. These results indicate that mitochondria- and PKC-dependent PTP are expressed at distinct hilar mossy fiber synapses depending on postsynaptic targets.
Interaction of Extracellular Signal-Regulated Protein Kinase 1/2 with Actin Cytoskeleton in Supraoptic Oxytocin Neurons and Astrocytes: Role in Burst Firing
Authors: Wang Yu-Feng , Hatton Glenn I.
Published: December 2007

Neuronal firing patterns determine the manner of neurosecretion, the underlying mechanisms of which are poorly understood. Using supraoptic nuclei in brain slices from lactating rats, we examined the involvement of extracellular signal-regulated protein kinase 1/2 (ERK1/2) and filamentous actin (F-actin) in burst generation by oxytocin (OT) neurons. Blocking phosphorylation of ERK1/2 (pERK1/2) decreased miniature EPSCs and blocked OT-evoked bursts, as did intracellularly loading an antibody against pERK1/2. OT (10 pm) increased cytosolic pERK1/2 close to the cell membrane within the first 5 min, subsiding by 30 min, whereas OT elicited pERK1/2 nuclear translocation in closely associated supraoptic astrocytes. The increased pERK1/2 was tightly correlated with spatiotemporal actin dynamics. In OT neurons, OT initially increased F-actin, particularly at membrane subcortical areas, and then decreased it after 30 min. Both polymerization and depolymerization of actin cytoskeleton were associated with bursts, but only polymerization facilitated OT-evoked bursts. Blocking ERK1/2 activation blocked OT-evoked actin polymerization, whereas depolymerizing F-actin increased pERK1/2 expression. These changes were further identifiedin vivo. In intact animals, suckling increased ERK1/2 activation in the cytosol and membrane subcortical area F-actin formation in OT neurons, whereas it increased F-actin concentration in astrocytic somata. Coimmunoprecipitation showed that suckling increased molecular interactions between pERK1/2 and actin. Finally, two different blockers of ERK1/2 kinase injected intracerebroventricularly reduced suckling-evoked milk ejections. This is the first demonstration that OT mediation of suckling-evoked bursts/milk ejections is via interactions between pERK1/2 and actin cytoskeleton.
Interactions between the NR2B Receptor and CaMKII Modulate Synaptic Plasticity and Spatial Learning
Authors: Zhou Yu , Takahashi Eiki , Li Weidong , Halt Amy , Wiltgen Brian , Ehninger Dan , Li Guo-Dong , Hell Johannes W. , Kennedy Mary B. , Silva Alcino J.
Published: December 2007

The NR2B subunit of the NMDA receptor interacts with several prominent proteins in the postsynaptic density, including calcium/calmodulin-dependent protein kinase II (CaMKII). To determine the function of these interactions, we derived transgenic mice expressing a ligand-activated carboxy-terminal NR2B fragment (cNR2B) by fusing this fragment to a tamoxifen (TAM)-dependent mutant of the estrogen receptor ligand-binding domain LBDG521R. Here, we show that induction by TAM allows the transgenic cNR2B fragment to bind to endogenous CaMKII in neurons. Activation of the LBDG521R-cNR2B transgenic protein in mice leads to the disruption of CaMKII/NR2B interactions at synapses. The disruption decreases Thr286 phosphorylation of αCaMKII, lowers phosphorylation of a key CaMKII substrate in the postsynaptic membrane (AMPA receptor subunit glutamate receptor 1), and produces deficits in hippocampal long-term potentiation and spatial learning. Together our results demonstrate the importance of interactions between CaMKII and NR2B for CaMKII activity, synaptic plasticity, and learning.
β1 Integrins in Radial Glia But Not in Migrating Neurons Are Essential for the Formation of Cell Layers in the Cerebral Cortex
Authors: Belvindrah Richard , Graus-Porta Diana , Goebbels Sandra , Nave Klaus-Armin , Müller Ulrich
Published: December 2007

Radial glial cells in the cerebral cortex serve as progenitors for neurons and glia and guide the migration of cortical neurons. The integrin α3β1 is thought to mediate interactions of migrating neurons with radial glial cells and to function as a receptor for the reelin signaling molecule. Here, we challenge this view and demonstrate that β1 integrins in migrating neurons are not essential for the formation of cell layers in the cerebral cortex. Cortical cell layers also form normally in mice deficient in the integrin α3β1. However, we provide evidence that β1 integrins in radial glia control the morphological differentiation of both glia and neurons. We conclude that β1 integrins in radial glia are required for the proper development of the cerebral cortex, whereas β1 integrins in migrating neurons are not essential for glial-guided migration and reelin signaling.
The Reacquisition of Biotin Prototrophy in Saccharomyces cerevisiae Involved Horizontal Gene Transfer, Gene Duplication and Gene Clustering
Authors: Hall Charles , Dietrich Fred S
Published: December 2007

The synthesis of biotin, a vitamin required for many carboxylation reactions, is a variable trait in Saccharomyces cerevisiae. Many S. cerevisiae strains, including common laboratory strains, contain only a partial biotin synthesis pathway. We here report the identification of the first step necessary for the biotin synthesis pathway in S. cerevisiae. The biotin auxotroph strain S288c was able to grow on media lacking biotin when BIO1 and the known biotin synthesis gene BIO6 were introduced together on a plasmid vector. BIO1 is a paralog of YJR154W, a gene of unknown function and adjacent to BIO6. The nature of BIO1 illuminates the remarkable evolutionary history of the biotin biosynthesis pathway in S. cerevisiae. This pathway appears to have been lost in an ancestor of S. cerevisiae and subsequently rebuilt by a combination of horizontal gene transfer and gene duplication followed by neofunctionalization. Unusually, for S. cerevisiae, most of the genes required for biotin synthesis in S. cerevisiae are grouped in two subtelomeric gene clusters. The BIO1–BIO6 functional cluster is an example of a cluster of genes of “dispensable function,” one of the few categories of genes in S. cerevisiae that are positionally clustered.
A Microsatellite Genetic Map of the Turbot (Scophthalmus maximus)
Authors: Bouza Carmen , Hermida Miguel , Pardo Belén G , Fernández Carlos , Fortes Gloria G , Castro Jaime , Sánchez Laura , Presa Pablo , Pérez Montse , Sanjuán Andrés , de Carlos Alejandro , Álvarez-Dios José Antonio , Ezcurra Susana , Cal Rosa M , Piferrer Francesc , Martínez Paulino
Published: December 2007

A consensus microsatellite-based linkage map of the turbot (Scophthalmus maximus) was constructed from two unrelated families. The mapping panel was derived from a gynogenetic family of 96 haploid embryos and a biparental diploid family of 85 full-sib progeny with known linkage phase. A total of 242 microsatellites were mapped in 26 linkage groups, six markers remaining unlinked. The consensus map length was 1343.2 cM, with an average distance between markers of 6.5 ± 0.5 cM. Similar length of female and male maps was evidenced. However, the mean recombination at common intervals throughout the genome revealed significant differences between sexes, ∼1.6 times higher in the female than in the male. The comparison of turbot microsatellite flanking sequences against the Tetraodon nigroviridis genome revealed 55 significant matches, with a mean length of 102 bp and high sequence similarity (81–100%). The comparative mapping revealed significant syntenic regions among fish species. This study represents the first linkage map in the turbot, one of the most important flatfish in European aquaculture. This map will be suitable for QTL identification of productive traits in this species and for further evolutionary studies in fish and vertebrate species.
Investigation of the Demographic and Selective Forces Shaping the Nucleotide Diversity of Genes Involved in Nod Factor Signaling in Medicago truncatula
Authors: De Mita Stéphane , Ronfort Joëlle , McKhann Heather I , Poncet Charles , El Malki Redouane , Bataillon Thomas
Published: December 2007

Symbiotic nitrogen-fixing rhizobia are able to trigger root deformation in their Fabaceae host plants, allowing their intracellular accommodation. They do so by delivering molecules called Nod factors. We analyzed the patterns of nucleotide polymorphism of five genes controlling early Nod factor perception and signaling in the Fabaceae Medicago truncatula to understand the selective forces shaping the evolution of these genes. We used 30 M. truncatula genotypes sampled in a genetically homogeneous region of the species distribution range. We first sequenced 24 independent loci and detected a genomewide departure from the hypothesis of neutrality and demographic equilibrium that suggests a population expansion. These data were used to estimate parameters of a simple demographic model incorporating population expansion. The selective neutrality of genes controlling Nod factor perception was then examined using a combination of two complementary neutrality tests, Tajima's D and Fay and Wu's standardized H. The joint distribution of D and H expected under neutrality was obtained under the fitted population expansion model. Only the gene DMI1, which is expected to regulate the downstream signal, shows a pattern consistent with a putative selective event. In contrast, the receptor-encoding genes NFP and NORK show no significant signatures of selection. Among the genes that we analyzed, only DMI1 should be viewed as a candidate for adaptation in the recent history of M. truncatula.
Inferring Human Population Sizes, Divergence Times and Rates of Gene Flow From Mitochondrial, X and Y Chromosome Resequencing Data
Authors: Garrigan Daniel , Kingan Sarah B , Pilkington Maya M , Wilder Jason A , Cox Murray P , Soodyall Himla , Strassmann Beverly , Destro-Bisol Giovanni , de Knijff Peter , Novelletto Andrea , Friedlaender Jonathan , Hammer Michael F
Published: December 2007

We estimate parameters of a general isolation-with-migration model using resequence data from mitochondrial DNA (mtDNA), the Y chromosome, and two loci on the X chromosome in samples of 25–50 individuals from each of 10 human populations. Application of a coalescent-based Markov chain Monte Carlo technique allows simultaneous inference of divergence times, rates of gene flow, as well as changes in effective population size. Results from comparisons between sub-Saharan African and Eurasian populations estimate that 1500 individuals founded the ancestral Eurasian population ∼40 thousand years ago (KYA). Furthermore, these small Eurasian founding populations appear to have grown much more dramatically than either African or Oceanian populations. Analyses of sub-Saharan African populations provide little evidence for a history of population bottlenecks and suggest that they began diverging from one another upward of 50 KYA. We surmise that ancestral African populations had already been geographically structured prior to the founding of ancestral Eurasian populations. African populations are shown to experience low levels of mitochondrial DNA gene flow, but high levels of Y chromosome gene flow. In particular, Y chromosome gene flow appears to be asymmetric, i.e., from the Bantu-speaking population into other African populations. Conversely, mitochondrial gene flow is more extensive between non-African populations, but appears to be absent between European and Asian populations.
The Evolution of Two Mutations During Clonal Expansion
Authors: Haeno Hiroshi , Iwasa Yoh , Michor Franziska
Published: December 2007

Knudson's two-hit hypothesis proposes that two genetic changes in the RB1 gene are the rate-limiting steps of retinoblastoma. In the inherited form of this childhood eye cancer, only one mutation emerges during somatic cell divisions while in sporadic cases, both alleles of RB1 are inactivated in the growing retina. Sporadic retinoblastoma serves as an example of a situation in which two mutations are accumulated during clonal expansion of a cell population. Other examples include evolution of resistance against anticancer combination therapy and inactivation of both alleles of a metastasis-suppressor gene during tumor growth. In this article, we consider an exponentially growing population of cells that must evolve two mutations to (i) evade treatment, (ii) make a step toward (invasive) cancer, or (iii) display a disease phenotype. We calculate the probability that the population has evolved both mutations before it reaches a certain size. This probability depends on the rates at which the two mutations arise; the growth and death rates of cells carrying none, one, or both mutations; and the size the cell population reaches. Further, we develop a formula for the expected number of cells carrying both mutations when the final population size is reached. Our theory establishes an understanding of the dynamics of two mutations during clonal expansion.
Differential Nuclear Localization Does Not Determine the Silencing Status ofSaccharomyces cerevisiaeTelomeres
Authors: Mondoux Michelle A , Scaife Jillian G , Zakian Virginia A
Published: December 2007

In Saccharomyces cerevisiae, genes near telomeres are transcriptionally repressed, a phenomenon termed telomere position effect (TPE). Yeast telomeres cluster near the nuclear periphery, as do foci of proteins essential for TPE: Rap1p, Sir2-4p, and yKu70p/yKu80p. However, it is not clear if localization of telomeres to the periphery actually contributes to TPE. We examined the localization patterns of two telomeres with different levels of TPE: truncated VII-L and native VI-R. For both telomeres, localization to the nuclear periphery or to the silencing foci was neither necessary nor sufficient for TPE. Moreover, there was no correlation between TPE levels and the extent of localization. Tethering the truncated VII-L telomere to the nuclear periphery resulted in a modest increase in TPE. However, tethering did not bypass the roles of yKu70p, Sir4p, or Esc1p in TPE. Using mutations in RIF genes that bypass the role of Ku in TPE, a correlation between the level of silencing and the number of Rap1p foci present in the nucleus was observed, suggesting that Sir protein levels at telomeres determine both the level of TPE and the number of foci.
The Tetrad-Pollen Model Fails to Explain the Bias in Mendel's Pea (Pisum sativum) Experiments
Authors: Fairbanks Daniel J , Schaalje G Bruce
Published: December 2007

For >40 years, geneticists and science historians have appealed to the tetrad-pollen model as an explanation of the bias toward expectation in Mendel's data, albeit without experimental support. Our experiments demonstrate that pollen sampling during self-pollination in pea conforms to the binomial distribution with no evidence of a tetrad-pollen effect.
Mapping Quantitative Trait Loci Affecting Susceptibility to Marek's Disease Virus in a Backcross Population of Layer Chickens
Authors: Heifetz E M , Fulton J E , O'Sullivan N P , Arthur J A , Wang J , Dekkers J C M , Soller M
Published: December 2007

Marek's disease (MD), caused by the oncogenic MD avian herpes virus (MDV), is a major source of economic losses to the poultry industry. A reciprocal backcross (BC) population (total 2052 individuals) was generated by crossing two partially inbred commercial Leghorn layer lines known to differ in MDV resistance, measured as survival time after challenge with a (vv+) MDV. QTL affecting resistance were identified by selective DNA pooling using a panel of 198 microsatellite markers covering two-thirds of the chicken genome. Data for each BC were analyzed separately, and as a combined data set. Markers showing significant association with resistance generally appeared in blocks of two or three, separated by blocks of nonsignificant markers. Defined this way, 15 chromosomal regions (QTLR) affecting MDV resistance, distributed among 10 chromosomes (GGA 1, 2, 3, 4, 5, 7, 8, 9, 15, and Z), were identified. The identified QTLR include one gene and three QTL associated with resistance in previous studies of other lines, and three additional QTL associated with resistance in previous studies of the present lines. These QTL could be used in marker-assisted selection (MAS) programs for MDV resistance and as a platform for high-resolution mapping and positional cloning of the resistance genes.
Synthetic Lethal Interactions Identify Phenotypic “Interologs” of the Spindle Assembly Checkpoint Components
Authors: Tarailo Maja , Tarailo Sanja , Rose Ann M
Published: December 2007

Here, we report genetic interactions with mdf-1(gk2)/MAD1 in Caenorhabditis elegans. Nine are evolutionarily conserved or phenotypic “interologs” and two are novel enhancers, hcp-1 and bub-3. We show that HCP-1 and HCP-2, the two CENP-F-related proteins, recently implicated in the spindle assembly checkpoint (SAC) function, do not have identical functions, since hcp-1(RNAi), but not hcp-2(RNAi), enhances the lethality of the SAC mutants.
A Measurable Increase in Oxidative Damage Due to Reduction in Superoxide Detoxification Fails to Shorten the Life Span of Long-Lived Mitochondrial Mutants of Caenorhabditis elegans
Authors: Yang Wen , Li Jingjing , Hekimi Siegfried
Published: December 2007

SOD-1 and SOD-2 detoxify superoxide in the cytoplasm and mitochondria. We find that, although several long-lived mutants of Caenorhabditis elegans have increased SOD levels, this phenomenon does not correlate with life span or growth rate. Furthermore, although disruption of sod-1 or -2 expression produces numerous phenotypes, including increased sensitivity to paraquat and increased oxidative damage to proteins (except in daf-2 mutants), this fails to shorten the life span of these long-lived mutants. In fact, sod-1(RNAi) increases the life span of daf-2 mutants and sod-2(RNAi) that of clk-1 mutants. Our results suggest that increased superoxide detoxification and low oxidative damage are not crucial for the longevity of the mutants examined, with the possible exception of daf-2, where our results are inconclusive. These results are surprising because several of the long-lived mutants that we examined specifically affect mitochondrial electron transport, a process whose involvement in life-span determination is believed to be related to superoxide generation. We discuss the significance of our findings in light of the oxidative stress theory of aging.
Investigating the Genetic Circuitry of Mastermind in Drosophila, a Notch Signal Effector
Authors: Kankel Mark W , Hurlbut Gregory D , Upadhyay Geeta , Yajnik Vijay , Yedvobnick Barry , Artavanis-Tsakonas Spyros
Published: December 2007

Notch signaling regulates multiple developmental processes and is implicated in various human diseases. Through use of the Notch transcriptional co-activator mastermind, we conducted a screen for Notch signal modifiers using the Exelixis collection of insertional mutations, which affects ∼50% of the Drosophila genome, recovering 160 genes never before associated with Notch, extending the previous roster of genes that interact functionally with the Notch pathway and mastermind. As the molecular identity for most recovered genes is known, gene ontology (GO) analysis was applied, grouping genes according to functional classifications. We identify novel Notch-associated GO categories, uncover nodes of integration between Notch and other signaling pathways, and unveil groups of modifiers that suggest the existence of Notch-independent mastermind functions, including a conserved ability to regulate Wnt signaling.
Deletion-Mutant mtDNA Increases in Somatic Tissues but Decreases in Female Germ Cells With Age
Authors: Sato Akitsugu , Nakada Kazuto , Shitara Hiroshi , Kasahara Atsuko , Yonekawa Hiromichi , Hayashi Jun-Ichi
Published: December 2007

The proportions of mutant and wild-type mtDNA are crucial in determining the severity of mitochondrial diseases. It has been generally considered that deletion-mutant mtDNA has replication advantages and accumulates with time. Here, we examine the tissue-by-tissue proportions of mutant mtDNA with a 4696-bp deletion (ΔmtDNA) and wild-type mtDNA in mitochondrial disease model mice (mito-mice). Comparison of the proportions of ΔmtDNA in each tissue at various ages showed that the rate of accumulation of ΔmtDNA differed among tissues. The heart, skeletal muscles, kidney, liver, testis, and ovary showed increases in the proportion of ΔmtDNA with age, but the pancreas, spleen, brain, and blood showed only a slight or no increase in proportion. In contrast to the somatic tissues, however, the germ cells of female mito-mice and resultant offspring showed a strong decrease in ΔmtDNA with maternal age. The decrease was so acute that some offspring showed complete disappearance of ΔmtDNA, even though their elder brothers and sisters had high proportions of ΔmtDNA. Female germ cells have a machinery that prevents the inheritence of defective mtDNA to the following generation since germ cells are kept for a long time until they are ovulated.
Multiple Functions and Dynamic Activation of MPK-1 Extracellular Signal-Regulated Kinase Signaling inCaenorhabditis elegansGermline Development
Authors: Lee Min-Ho , Ohmachi Mitsue , Arur Swathi , Nayak Sudhir , Francis Ross , Church Diane , Lambie Eric , Schedl Tim
Published: December 2007

The raison d'etre of the germline is to produce oocytes and sperm that pass genetic material and cytoplasmic constituents to the next generation. To achieve this goal, many developmental processes must be executed and coordinated. ERK, the terminal MAP kinase of a number of signaling pathways, controls many aspects of development. Here we present a comprehensive analysis of MPK-1 ERK in Caenorhabditis elegans germline development. MPK-1 functions in four developmental switches: progression through pachytene, oocyte meiotic maturation/ovulation, male germ cell fate specification, and a nonessential function of promoting the proliferative fate. MPK-1 also regulates multiple aspects of cell biology during oogenesis, including membrane organization and morphogenesis: organization of pachytene cells on the surface of the gonadal tube, oocyte organization and differentiation, oocyte growth control, and oocyte nuclear migration. MPK-1 activation is temporally/spatially dynamic and most processes appear to be controlled through sustained activation. MPK-1 thus may act not only in the control of individual processes but also in the coordination of contemporaneous processes and the integration of sequential processes. Knowledge of the dynamic activation and diverse functions of MPK-1 provides the foundation for identification of upstream signaling cascades responsible for region-specific activation and the downstream substrates that mediate the various processes.
Cell Cycle Arrest of Stamen Initials in Maize Sex Determination
Authors: Kim Jong Cheol , Laparra Hélène , Calderón-Urrea Alejandro , Mottinger John P , Moreno Maria A , Dellaporta Stephen L
Published: December 2007

The maize sex determination pathway results in the arrest of stamen in ear spikelets and the abortion of pistils in both the tassel spikelets and in the secondary florets of ear spikelets. Arrested stamen cells showed no signs of DNA fragmentation, an absence of CYCLIN B expression, and an accumulation of the negative cell cycle regulator WEE1 RNA.
Changes in Vitamin Status of Indian Antarctic Expeditioners During a One-Month Stay in Austral Summer
Authors: Vats Praveen , Singh Som N. , Singh Vijay K. , Shyam Radhey , Upadhyay Tribhuvan N. , Singh Shashi B. , Banerjee Pratul K.
Published: December 2007

Objective

Antarctic expeditioners face extremes of environmental conditions along with isolation which affect normal human activity at a polar station. Diets of polar expeditioners consist of products that have been kept in storage for more than a year. Processing and preservation adversely affect the nutritive value of the food products, especially water-soluble vitamins. This study was conducted to determine water-soluble vitamin status of Antarctic expeditioners consuming processed canned food.

Methods

Twenty-two healthy male volunteers age 26 to 56 years (39.5 ± 8.5, mean ± SD) participated in the study. The study was conducted in 3 phases: at Goa, India (phase I), 48 hours after arriving in Antarctica (phase II) and after 1 month in Antarctica (phase III). Water-soluble vitamin status in erythrocytes was assessed at each phase with evaluation of riboflavin, thiamine, and pyridoxine status. Urinary N-methyl nicotinamide and methylmalonic acid (MMA) levels were measured to assess niacin and vitamin B12 status. Blood plasma assays were used to assess ascorbic acid status.

Results

No significant changes in riboflavin, thiamine, and pyridoxine status in erythrocytes and urinary excretion levels were observed after 1 month in Antarctica. Vitamin C levels decreased significantly ( P < .001) after 1 month in Antarctica compared with basal values (1.31 ± 0.076 mg/dL during phase I to 0.81 ± 0.063 mg/dL during phase III). However, these levels were still within the normal reference range.

Conclusion

This study found no water-soluble vitamin deficiencies in participants consuming processed and canned food after 1 month in Antarctica.
Ginkgo biloba Decreases Acute Mountain Sickness in People Ascending to High Altitude at Ollagüe (3696 m) in Northern Chile
Authors: Moraga Fernando A. , Flores Alejandro , Serra Jordi , Esnaola Carla , Barriento Corina
Published: December 2007

Objective

To determine the prophylactic effect of Ginkgo biloba (doses 80 mg/12 h, 24 h before high-altitude ascension and with continued treatment) in preventing acute mountain sickness (AMS) at 3696 m in participants without high-altitude experience.

Methods

Thirty-six participants who reside at sea level were transported to an altitude of 3696 m (Ollagüe). The participants were divided into 3 groups and received G biloba ( n = 12) 80 mg/12 h, acetazolamide ( n = 12) 250 mg/12 h, or placebo ( n = 12) 24 hours before ascending and during their 3-day stay at high altitude. The Lake Louise Questionnaire constituted the primary outcome measurement at sea level and at 3696 m. A Lake Louise Self-Report Score greater than 3 was indicative of AMS. Oxygen saturation, heart rate, and arterial pressure were taken with each evaluation for AMS.

Results

A significant reduction in AMS was observed in the group that received G biloba (0%, P < .05) comparison with the groups receiving acetazolamide (36%, P < .05) or placebo (54%). No difference was observed in arterial oxygen saturation in the G biloba (92 ± 2) vs the acetazolamide (89 ± 2) groups. However, a marked increased saturation in arterial oxygen was seen in comparison with the placebo group (84 ± 3, P < .05). No statistically significant differences were observed in mean arterial pressure or heart rate.

Conclusions

This study provides evidence supporting the use of G biloba in the prevention of AMS, demonstrating that 24 hours of pretreatment with G biloba and subsequent maintenance during exposure to high altitude are sufficient to reduce the incidence of AMS in participants with no previous high-altitude experience.
Snakebite Injuries Treated in United States Emergency Departments, 2001–2004
Authors: O’Neil Mary Elizabeth , Mack Karin A. , Gilchrist Julie , Wozniak Edward J.
Published: December 2007

Objective

Venomous and nonvenomous snakes are found throughout most of the United States. While the literature on treatment is robust, there is not a current national epidemiologic profile of snakebite injuries in the United States. National estimates of such injuries treated in emergency departments (EDs) are presented along with characteristics of the affected population.

Methods

Data on snakebite injuries were abstracted from the National Electronic Injury Surveillance System–All Injury Program (2001–04). Variables included age, gender, body part affected, cause, disposition, and treatment date. When available, location, intentionality of the interaction, and snake species were coded based on narrative comments. Estimates were weighted and analyzed with SPSS Complex Samples.

Results

An estimated 9873 snakebites were treated in US EDs each year between 2001 and 2004. Males were more frequently seen in the ED for snakebites than were females (males: 72.0% [95% confidence interval (CI), 68.0–75.7]; females: 28.0% [95% CI, 24.3–32.0]). Approximately 32% of patients were known to be bitten by venomous species. Overall, more than one quarter of patients were hospitalized (27.9% [95% CI, 15.9–44.2]), although 58.9% of patients with known venomous bites were hospitalized (95% CI, 41.5–74.3).

Conclusions

While they are rare events, snakebites cause nearly 10 000 visits to EDs for treatment every year. Epidemiologic data regarding snakebites provide practicing physicians with an understanding of the population affected and can help guide public health practitioners in their prevention efforts.
Animal-Caused Fatalities in New Mexico, 1993–2004
Authors: Lathrop Sarah L.
Published: December 2007

Objective

To evaluate animal-caused fatalities in New Mexico using data collected during medicolegal death investigations, including toxicology, survival interval, and circumstances.

Methods

A retrospective review of the computerized database and hard copies of files from a centralized, statewide medical examiner's office, excluding deaths due to zoonotic diseases and motor vehicle collisions involving animals.

Results

Between 1993 and 2004, 63 deaths caused by animals were reported in New Mexico. The majority of decedents were male (46/63, 73%) and non-Hispanic white (33/63, 52%). Horses were the most commonly implicated animals, with 43 (68%) deaths due to a person being thrown from, crushed, dragged, or kicked by a horse. Cattle caused 9 deaths (14%), dogs caused 3 (5%), and venomous animals caused 3, whereas a bear was responsible for 1 death. Ten decedents (16%) had alcohol present at the time of death, and 8 would have been over the legal blood alcohol concentration for driving (0.08%). Ten deaths (16%) were work-related and included deaths of jockeys and ranch workers. The majority of deaths (42/63, 67%) occurred in remote locations, potentially delaying access to treatment. Survival intervals ranged from 1 day to 33 years.

Conclusions

Whereas both human and animal behavior can be difficult to predict, a review of animal-caused fatalities investigated by a medical examiner revealed that in many cases, deaths could have been prevented by either the use of protective gear or alterations in human behavior.
Medical Incidents and Evacuations on Wilderness Expeditions
Authors: McIntosh Scott E. , Leemon Drew , Visitacion Joshua , Schimelpfenig Tod , Fosnocht David
Published: December 2007

Objective

Expedition activities such as mountaineering, rock climbing, river running, sea kayaking, and canoeing all involve an element of risk. Organizations that provide group wilderness and adventure experiences are responsible for managing the risk of their courses. The leaders and medical providers of these trips must therefore be prepared to anticipate and manage medical problems that may arise. The aim of this study is to provide the medical community with a better understanding of the specific injuries and illnesses that occur on wilderness expeditions.

Methods

A retrospective descriptive study was done examining the medical incidents that occurred on wilderness-based courses during the 3-year period from September 1, 2002, through August 31, 2005. Participants and staff of the National Outdoor Leadership School (NOLS) served as the study population.

Results

Injuries occurred at a rate of 1.18 per 1000 program days, and illnesses at a rate of 1.08 per 1000 program days. There were no fatalities during the time period. Athletic injuries (sprains, strains) and gastrointestinal illnesses were the most common medical incidents. Hypothermia, seizures, appendicitis, heat stroke, and pregnancy occurred but with low frequency. Fractures, dental emergencies, tick fever, athletic injuries, and nonspecific body pains were the conditions most frequently requiring evacuation.

Conclusions

The rate of medical incidents on NOLS courses declined during the 1990s and has remained relatively steady apart from a slight increase in 2004 and 2005. Athletic injuries continue to be a difficulty, as they frequently result in evacuation even though their ultimate outcome is usually benign. Evacuation decisions should be made considering both the potential severity of the medical condition as well as patient comfort. Wilderness medical personnel must be familiar with a diverse range of medical conditions in order to provide optimal care.
Pulmonary Artery Pressure in Healthy Subjects at 4250 m Measured by Doppler Echocardiography
Authors: Dubowitz Gerald , Peacock Andrew J.
Published: December 2007

Objective

Acute hypoxia causes vasoconstriction in the pulmonary arteries. This hypoxic pulmonary vasoconstriction (HPV) has been reported to be common in subjects exposed to high altitude. In the past, it has been difficult to directly measure this HPV because of the invasive nature of tests, but the recent availability of portable color flow Doppler ultrasound has enabled measurements of pulmonary artery systolic pressure (PASP) in the field. We set out to study the feasibility of this method to detect changes related to HPV at 4250 m. We hypothesized that significant changes in the cardiopulmonary circulation are seen at high altitude and are detectable with Doppler echocardiography. In addition, we hypothesized that detected changes are related to the syndrome of acute mountain sickness (AMS) and could be reversed using 100% oxygen.

Methods

Over a 10-week period in the spring of 1998, 56 healthy lowlanders not normally residing at altitude were studied while visiting 4250 m in Nepal having walked from 2774 m. This was a cross-sectional observational study conducted by a single experienced observer at high altitude, using transthoracic color flow continuous wave Doppler echocardiography. Subjects were initially assessed for significant tricuspid regurgitation (TR) to measure PASP. After estimating PASP under ambient conditions at altitude, oxygen was delivered and PASP remeasured.

Results

Of 56 subjects, 36 had Doppler signals appropriate for estimation of pulmonary artery systolic pressure. In these 36, a wide range of PASP was observed (mean 25 mm Hg, range 18–36 mm Hg), but none fell outside of the normal range. After oxygen administration, PASP was reduced (from mean 25 mm Hg to mean 18 mm Hg, P < .0001) suggesting that a degree of hypoxic pulmonary vasoconstriction was present. No subjects in the study group reported clinical AMS.

Conclusions

We found PASP at 4250 m to be within the normal range but higher than would be expected at sea level; however, unlike previous reports, we found such increases to be mild and reversible with oxygen. In addition, the observed incidence of AMS was low when compared with earlier studies, perhaps related to adequate acclimatization.
Cognitive function assessment in idiopathic Parkinson's disease
Authors: Piovezan Mauro R. , Teive Helio A.G. , Piovesan Elcio J. , Mader Maria J. , Werneck Lineu Cesar
Published: December 2007

Idiopathic Parkinson’s disease (PD) is characterized by reduced nigrostriatal and cortical dopaminergic influence, with changes in movement and, subsequently, behavioral and cognitive disturbances. We studied cognitive impairment in Parkinson’s disease by assessing a group of 30 idiopathic Parkinson’s disease patients with an average age of 64.23 years (PG group) and compared our findings with those for a control group of 30 patients (CG group). All the patients were submitted to the following assessments: motor function, using the UPDRS; staging, using the Hoehn-Yahr scales (PG group only); depression, using the Montgomery-Asberg scale; attention impairment; verbal fluency (FAR and animals); cognitive function, using the Mini Mental State Examination; visuospatial and executive functions; and clock drawing. In addition to altered motor function in PD patients, we found statistically significant differences between PD patients and controls in terms of cognitive function, verbal, executive and visuospatial functions, and attention deficits. Depression was more prevalent in the PG group.
The effects of bromazepam on the early stage of visual information processing (P100)
Authors: Puga Fernanda , Sampaio Isabel , Veiga Heloisa , Ferreira Camila , Cagy Maurício , Piedade Roberto , Ribeiro Pedro
Published: December 2007

The early stages of visual information processing, involving the detection and perception of simple visual stimuli, have been demonstrated to be sensitive to psychotropic agents. The present study investigated the effects of an acute dose of bromazepam (3 mg), compared with placebo, on the P100 component of the visual evoked potential and reaction time. The sample, consisting of 14 healthy subjects (6 male and 8 female), was submitted to a visual discrimination task, which employed the "oddball" paradigm. Results suggest that bromazepam (3 mg) impairs the initial stage of visual information processing, as observed by an increase in P100 latency.