The Tick-Tock of Language: Is Language Processing Sensitive to Circadian Rhythmicity and Elevated Sleep Pressure?

The master circadian pacemaker emits signals that trigger organ-specific oscillators and, therefore, constitutes a basic biological process that enables organisms to anticipate daily environmental changes by adjusting behavior, physiology, and gene regulation. Although circadian rhythms are well characterized on a physiological level, little is known about circadian modulations of higher cognitive functions. Thus, we investigated circadian repercussions on language performance at the level of minimal syntactic processing by means of German noun phrases in ten young healthy men under the unmasking conditions of a 40 h constant-routine protocol. Language performance for both congruent and incongruent noun phrases displayed a clear diurnal rhythm with a peak performance decrement during the biological night. The nadirs, however, differed such that worst syntactic processing of incongruent noun phrases occurred 3 h earlier (07:00 h) than that of congruent noun phrases (10:00 h). Our results indicate that language performance displays an internally generated circadian rhythmicity with optimal time for parsing language between 3 to 6 h after the habitual wake time, which usually corresponds to 10:00–13:00 h. These results may have important ramifications for establishing optimal times for shiftwork changes or testing linguistically impaired people.     

Circadian Rhythm of Serotonin Binding in Rat Brain—II. Influence of Sleep Deprivation and Imipramine

Sleep deprivation (SD) modified the circadian rhythm of specific high affinity serotonin (5-HT) binding to rat brain membranes. In control rats a 24-hr rhythm was evident with a trough at 1000-1200 and a nadir at 0000. During the last 26 hr of a 49 hr SD period, trough and peak values were delayed by 4-6 hr. The 24-hr mean binding was significantly (P < 0.001) different from that of controls. If sleep deprivation was followed by recovery sleep (RS), the normal rhythm of 5-HT binding was obtained already within 1 hr after SD. The effects of SD and RS were ascertained by plasma ACTH and corticosterone assay. No significant change in the hormone rhythms were observed though the mean plasma level of ACTH and corticosterone were enhanced to about 180 and 150%, respectively. Chronic treatment with the antidepressant imipramine resulted in a decrease of the 24-hr mean 5-HT binding by about 50% and a 2-hr delay of peak and trough values. Imipramine treatment decreased the peak valueof 5-HT concentration at 1000 to about 65% and appears to abolish the rhythm of 5-HT concentration.     

CONGENITAL ABNORMALITIES—The Timing and Management of Surgical Reconstruction in Infancy and Childhood

The proper timing of corrective and reconstructive surgical operations for the management of congenital abnormalities in infancy and childhood is exceptionally important. Although no hard and fast rules apply, each deformity should be evaluated in the light of specific features of local and general relationship. Correlation to growth and development must be stressed as an important feature. Evaluation of the congenital abnormality in the light of its many relationships provides for a basis of better complete handling, follow-up, and ultimate result with the aim directed toward elimination of tumor threat, restoration of function and esthetic improvement.     

The Occurence of δ-Tocopherylquinone in Higher Plants and Its Relation to Senescence

δ-Tocopherylquinone (δTQ) content was determined in tobacco and yellow maple leaves, green ivy leaves and cactus tissues. It was found that the concentration of δ-TQ was highest in mature or senescent tissues, such as white tobacco leaves (0.02 μmole/g dry wt) while its detection was uncertain in young, green leaves from the apex of tobacco plants. Fractionation by centrifugation of senescent tobacco leaves showed that the osmiophilic globule fraction was enriched in δ-TQ. Electron microscope studies of young, mature and senescent tobacco tissues showed progressive changes in the size and number of osmiophilic globules. After chloroplast breakdown in senescent tobacco leaves, these globules became the predominant constituents of the organelle. δ-TQ which is associated with osmiophilic globules may play a role in the development of plants, particularly during senescence.     

Molecular Clocks and the Timing of the Placental and Marsupial Radiations in Relation to the Cretaceous–Tertiary Boundary

Paleostratigraphic estimates of divergence time for nine independent cladogenic events within Mammalia, ranging from 14 to 130 million years, were regressed against Tamura–Nei-corrected 12S rRNA transversions. Relative rate-adjusted distances were also regressed against paleostratigraphic divergence times. The resulting equations were used to estimate interordinal divergence times within Eutheria and Metatheria for a data set that includes representatives of all orders in each infraclass. Without the adjustment for rate variation, divergence times range from 34 to 156 million years for placental orders, versus 32 to 86 million years for marsupial orders. With rate adjustments, the range of divergence estimates decreases to 53 to 133 million years for placentals versus 40 to 79 million years for marsupials. The effect of rate adjustments is most noticeable for carnivores and perissodactyls, where rates are slow, and proboscideans, where rates are fast. In agreement with studies based on nuclear genes, both unadjusted and rate-adjusted estimates of sequence divergence indicate that the majority of placental orders originated before the terminal Cretaceous extinction. Exceptions include the perissodactyl–carnivore split and cladogenesis among paenungulate orders. Most marsupial orders, in turn, may have originated in the early Tertiary although didelphimorphs, at least, appear to have split from other lineages in the late Cretaceous. Marsupial divergence times based on 12S rRNA data are in good agreement with estimates based on single-copy DNA hybridization and disagree with the suggestion of Hershkovitz (1992) that Dromiciops separated from other marsupials in the Jurassic.     

The Patterns of Secretory Structure and Their Relation to Hypericin Content in Hypericum

金丝桃属植物分泌结构的类型和金丝桃素含量的相关性 吕洪飞^1,2 沈宗根¹ 李景原¹ 胡正海^1**     

Role of TLR4/NF-κB in Damage to Intestinal Mucosa Barrier Function and Bacterial Translocation in Rats Exposed to Hypoxia

The role of Toll-like receptor 4 (TLR4)/nuclear factor-kappa-B (NF-κB) in intestinal mucosal barrier damage and bacterial translocation under hypoxic exposure is unclear. Here, we investigated their role using an acute hypobaric hypoxia model. Adult Sprague-Dawley rats were divided into control (C), hypoxia (H), hypoxia+NF-κB inhibitor pyrrolidinedithiocarbamic acid (PDTC) (100 mg. kg) (HP), hypoxia+0.5 mg/kg lipopolysaccharide (HPL), and hypoxia+PDTC+LPS (HPL) group. Except control group, other four groups were placed in a hypobaric chamber set at 7000 m. Samples were collected at 72 h after pressure reduction. Damage in ultrastructure of the intestinal tract was examined by transmission electron microscopy and bacterial translocation was detected by cultivation. Kinetic turbidimetric assay was used to measure the serum LPS.ELISA was performed to detect TNF-α and IL-6 serum concentrations. Fluorescent quantitative RT-PCR was used to measure TLR4 mRNA levels was measured using quantitative RT-PCR and protein of NF-κB p65 was measured by western blotting. Different degrees of intestinal mucosa damage were observed in groups H and HL. The damage was significantly alleviated after blockage of the TLR4/NF-κB signaling pathway. PDTC- treatment also reversed hyoxia- and LPS-induced bacterial translocation rate and increased serum levels of LPS, TNF-α, and IL-6. TLR4 mRNA levels and NF-κB p65 expression were consistent with the serum factor results. This study suggested that TLR4 and NF-κB expression increased in rat intestinal tissues after acute hypoxia exposure. PDTC-treatment reversed TLR4 and NF-κB upregulation and alleviated damage to the intestinal tract and bacterial translocation. Thus, the TLR4/NF-κB signaling pathway may be critical to the mechanism underlying hypoxia-induced damage to intestinal barrier function and bacterial translocation.     

Specific Binding and Characteristics of 18β-Glycyrrhetinic Acid in Rat Brain

18β-Glycyrrhetinic acid (GA) is the aglycone of glycyrrhizin that is a component of Glycyrrhiza, and has several pharmacological actions in the central nervous system. Recently, GA has been demonstrated to reach the brain by crossing the blood-brain barrier in rats after oral administration of a Glycyrrhiza-containing traditional Japanese medicine, yokukansan. These findings suggest that there are specific binding sites for GA in the brain. Here we show evidence that [³H]GA binds specifically to several brain areas by quantitative autoradiography; the density was higher in the hippocampus, moderate in the caudate putamen, nucleus accumbens, amygdala, olfactory bulb, cerebral cortex, thalamus, and mid brain, and lower in the brain stem and cerebellum. Several kinds of steroids, gap junction-blocking reagents, glutamate transporter-recognized compounds, and glutamate receptor agonists did not inhibit the [³H]GA binding. Microautoradiography showed that the [³H]GA signals in the hippocampus were distributed in small non-neuronal cells similar to astrocytes. Immunohistochemical analysis revealed that immunoreactivity of 11β-hydroxysteroid dehydrogenase type-1 (11β-HSD1), a defined molecule recognized by GA, was detected mainly in neurons, moderately in astrocytes, and very slightly in microglial cells, of the hippocampus. These results demonstrate that specific binding sites for GA exist in rat brain tissue, and suggest that the pharmacological actions of GA may be related to 11β-HSD1 in astrocytes. This finding provides important information to understand the pharmacology of GA in the brain.     

Is the Fatty Acid Composition of Phospholipids Important for the Function of the Circadian Clock in Neurospora crassa?

Effects of pheriylmethanol (PM), 2-phenylethanol (PE) and 3-phenyl-1-propanol(PP) on the conidiation rhythm and on the fatty acid compositionof phospholipids were examined in Neurospora crassa. The periodfor the conidiation rhythm was shortened in proportion to theconcentration used of PE of more than 1 mM. PM at 10 mM andPP at 3 mM, however, did not cause a decrease in the lengthof the period. PE did not affect the temperature compensationof the length of the period or the amplitude of the phase shiftby light. The ratio of linolenic acid to Hnoleic acid decreased in proportionto the concentrations of PE, PM, and PP in all the phospholipidsexamined. The proportion of phosphatidic acid+diphosphatidylglycerolto the total phospholipids also was decreased by these compounds.Period shortening by PE can not be explained by the change inthe phospholipid fatty acid composition. (Received April 18, 1983; Accepted June 22, 1983)     

The Problem of Colliding Networks and its Relation to Cell Fusion and?Cancer

Cell fusion, a process that merges two or more cells into one, is required for normal development and has been explored as a tool for stem cell therapy. It has also been proposed that cell fusion causes cancer and contributes to its progression. These functions rely on a poorly understood ability of cell fusion to create new cell types. We suggest that this ability can be understood by considering cells as attractor networks whose basic property is to adopt a set of distinct, stable, self-maintaining states called attractors. According to this view, fusion of two cell types is a collision of two networks that have adopted distinct attractors. To learn how these networks reach a consensus, we model cell fusion computationally. To do so, we simulate patterns of gene activities using a formalism developed to simulate patterns of memory in neural networks. We find that the hybrid networks can assume attractors that are unrelated to parental attractors, implying that cell fusion can create new cell types by nearly instantaneously moving cells between attractors. We also show that hybrid networks are prone to assume spurious attractors, which are emergent and sporadic network states. This finding means that cell fusion can produce abnormal cell types, including cancerous types, by placing cells into normally inaccessible spurious states. Finally, we suggest that the problem of colliding networks has general significance in many processes represented by attractor networks, including biological, social, and political phenomena.     

Induction of Rat Prolactinoma by β－Estradiol and Its Relation to Expression of c－myc Oncogene

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The Relationship Between Src-Suppressed C Kinase Substrate and ��-1,4 Galactosyltransferase-I in the Process of Lipopolysaccharide-Induced TNF-�� Secretion in Rat Primary Astrocytes

Src-suppressed C kinase substrate (SSeCKS), a protein kinase C substrate, is a major lipopolysaccharide (LPS) response protein. In addition, β-1,4 Galactosyltransferase-I (β-1,4-GalT-I) also plays an important role in the inflammation reactions of nervous system. It was reported that both SSeCKS and β-1,4-GalT-I were involved in the LPS-induced tumor necrosis factor-alpha (TNF-α) expression in rat primary astrocytes. However, the functional interaction between SSeCKS and β-1,4-GalT-I in the LPS-induced TNF-α secretion remains unclear. Therefore, in this study, using the inflammation model of astrocytes treated by LPS in vitro, we found that the changed expressions of SSeCKS and β-1,4-GalT-I participated in LPS-induced TNF-α secretion through p38, JNK, and ERK signal transduction pathways in rat primary astrocytes. Knockdown by small-interfering RNAs (siRNAs) or overexpression of SSeCKS and β-1,4-GalT-I could influence Mitogen-activated protein kinases (MAPKs) signaling pathways activation and TNF-α secretion. Besides, we confirmed that knockdown of SSeCKS could prevent the induction of β-1,4-GalT-I in this process. Inversely, β-1,4-GalT-I had no significant effect on SSeCKS expression in the same way. In summary, our data indicated that SSeCKS could regulate LPS-induced TNF-α secretion through β-1,4-GalT-I in rat primary astrocytes.     

Cytokine and Nitric Oxide Levels in Patients with Sepsis – Temporal Evolvement and Relation to Platelet Mitochondrial Respiratory Function

Background

The levels of nitric oxide (NO) and various cytokines are known to be increased during sepsis. These signaling molecules could potentially act as regulators and underlie the enhancement of mitochondrial function described in the later phase of sepsis. Therefore, we investigated the correlation between observed changes in platelet mitochondrial respiration and a set of pro- and anti-inflammatory cytokines as well as NO plasma levels in patients with sepsis.

Methods and Results

Platelet mitochondrial respiration and levels of TNFα, MCP-1 (monocyte chemotactic protein-1), INFγ (interferon-γ), IL-1β, IL-4, IL-5, IL-6, IL-8, IL-10 and IL-17 and NO were analyzed in 38 patients with severe sepsis or septic shock at three time points during one week following admission to the ICU. Citrate synthase, mitochondrial DNA and cytochrome c were measured as markers of cellular mitochondrial content. All mitochondrial respiratory states increased over the week analyzed (p<0.001). IL-8 levels correlated with maximal mitochondrial respiration on day 6–7 (p = 0.02, r² = 0.22) and was also higher in non-survivors compared to survivors on day 3–4 and day 6–7 (p = 0.03 respectively). Neither NO nor any of the other cytokines measured correlated with respiration or mortality. Cytochrome c levels were decreased at day 1–2 by 24±5% (p = 0.03) and returned towards values of the controls at the last two time points. Citrate synthase activity and mitochondrial DNA levels were similar to controls and remained constant throughout the week.

Conclusions

Out of ten analyzed cytokines and nitric oxide, IL-8 correlated with the observed increase in mitochondrial respiration. This suggests that cytokines as well as NO do not play a prominent role in the regulation of platelet mitochondrial respiration in sepsis. Further, the respiratory increase was not accompanied by an increase in markers of mitochondrial content, suggesting a possible role for post-translational enhancement of mitochondrial respiration rather than augmented mitochondrial mass.