Interleukin-6 regulates hepatic transporters during acute-phase response

Cholestasis develops during inflammatory conditions characterized by the release of cytokines like interleukin-6 (IL-6), which is the major player in the hepatic acute-phase response. However, the exact contribution of IL-6 to transporter down-regulation is unclear. Therefore, we compared wild-type and IL-6-deficient mice after IL-6-injection and induction of an aseptic (turpentine-injection) or septic (LPS-injection) acute-phase response. Down-regulation of basolateral (Ntcp, Oatp1, and Mrp3) and canalicular (Mrp2, Bsep) transporter mRNA occurred after treatment with IL-6, turpentine, and LPS. In IL-6-deficient mice, turpentine failed to decrease mRNA-levels of basolateral and canalicular transporters, whereas LPS-mediated down-regulation of Ntcp, Mrp3, and Mrp2 was abolished at later time points (24 h). In conclusion, induction of an aseptic and septic acute-phase response leads to the down-regulation of basolateral and canalicular organic anion transporters. IL-6 is required for transporter down-regulation during aseptic inflammation. Furthermore, IL-6 also contributes to transporter regulation during LPS-induced cholestasis at more delayed time points.     

Internal friction controls the speed of protein folding from a compact configuration

Several studies have found millisecond protein folding reactions to be controlled by the viscosity of the solvent: Reducing the viscosity allows folding to accelerate. In the limit of very low solvent viscosity, however, one expects a different behavior. Internal interactions, occurring within the solvent-excluded interior of a compact molecule, should impose a solvent-independent upper limit to folding speed once the bulk diffusional motions become sufficiently rapid. Why has this not been observed? We have studied the effect of solvent viscosity on the folding of cytochrome c from a highly compact, late-stage intermediate configuration. Although the folding rate accelerates as the viscosity declines, it tends toward a finite limiting value approximately 10(5) s(-1) as the viscosity tends toward zero. This limiting rate is independent of the cosolutes used to adjust solvent friction. Therefore, interactions within the interior of a compact denatured polypeptide can limit the folding rate, but the limiting time scale is very fast. It is only observable when the solvent-controlled stages of folding are exceedingly rapid or else absent. Interestingly, we find a very strong temperature dependence in these "internal friction"-controlled dynamics, indicating a large energy scale for the interactions that govern reconfiguration within compact, near-native states of a protein.     

Differential lipid affinity of xenobiotics and natural compounds

Octanol-1/water partitioning currently provides the most widely used model system to simulate both phospholipid target lipids and triglyceride storage lipids. A differentiation between the two lipid classes is now achieved by making use of a water-induced lipid phase separation. Coefficients (K(TG/PC)) for partitioning between trioleoylglycerol (TG) and phosphatidylcholine (PC) were determined for 20 xenobiotics and two biological lipids. K(TG/PC) values are related to KOW through the relationship, log K(TG/PC)=0.33 log KOW-1.078. The present results will allow better predictions on whether drugs and xenobiotics are bioaccumulated, degraded or reach toxicity-related sites. In addition, applications to natural lipophilic compounds and disease-related proteins are discussed.     

Sudden exposure to solar UV-B radiation reduces net CO(2) uptake and photosystem I efficiency in shade-acclimated tropical tree seedlings

Tree seedlings developing in the understory of the tropical forest have to endure short periods of high-light stress when tree-fall gaps are formed, and direct solar radiation, including substantial UV light, reaches the leaves. In experiments simulating the opening of a tree-fall gap, the response of photosynthesis in leaves of shade-acclimated seedlings (Anacardium excelsum, Virola surinamensis, and Calophyllum longifolium) to exposure to direct sunlight (for 20-50 min) was investigated in Panama (9 degrees N). To assess the effects of solar UV-B radiation (280-320 nm), the sunlight was filtered through plastic films that selectively absorbed UV-B or transmitted the complete spectrum. The results document a strong inhibition of CO(2) assimilation by sun exposure. Light-limited and light-saturated rates of photosynthetic CO(2) uptake by the leaves were affected, which apparently occurred independently of a simultaneous inhibition of potential photosystem (PS) II efficiency. The ambient UV-B light substantially contributed to these effects. The photochemical capacity of PSI, measured as absorbance change at 810 nm in saturating far-red light, was not significantly affected by sun exposure of the seedlings. However, a decrease in the efficiency of P700 photooxidation by far-red light was observed, which was strongly promoted by solar UV-B radiation. The decrease in PSI efficiency may result from enhanced charge recombination in the reaction center, which might represent an incipient inactivation of PSI, but contributes to thermal dissipation of excessive light energy and thereby to photoprotection.     

Circadian dynamics of cytosolic and nuclear Ca2+ in single suprachiasmatic nucleus neurons

Intracellular free Ca(2+) regulates diverse cellular processes, including membrane potential, neurotransmitter release, and gene expression. To examine the cellular mechanisms underlying the generation of circadian rhythms, nucleus-targeted and untargeted cDNAs encoding a Ca(2+)-sensitive fluorescent protein (cameleon) were transfected into organotypic cultures of mouse suprachiasmatic nucleus (SCN), the primary circadian pacemaker. Circadian rhythms in cytosolic but not nuclear Ca(2+) concentration were observed in SCN neurons. The cytosolic Ca(2+) rhythm period matched the circadian multiple-unit-activity (MUA)-rhythm period monitored using a multiple-electrode array, with a mean advance in phase of 4 hr. Tetrodotoxin blocked MUA, but not Ca(2+) rhythms, while ryanodine damped both Ca(2+) and MUA rhythms. These results demonstrate cytosolic Ca(2+) rhythms regulated by the release of Ca(2+) from ryanodine-sensitive stores in SCN neurons.     

A retrospective analysis of the clinical case records of 'autistic psychopaths' diagnosed by Hans Asperger and his team at the University Children's Hospital,Vienna

To date, it is questionable whether the diagnostic criteria for Asperger syndrome (AS) as stated by ICD-10 or DSM-IV still reflect Asperger's original account of 'autistic psychopathy' (AP) from the 1940s. The present study examined 74 clinical case records of children with AP diagnosed by Hans Asperger and his team at the Viennese Children's Clinic and Asperger's private practice between 1950 and 1986. The characteristic features of the children are outlined, including reasons for referral, parental background, behavioural problems, cognitive functioning, communication and interests. Results show that the patients of Asperger described in our study represent a subgroup of children with very high intellectual functioning, specific circumscribed interests and talents but impaired social, communication and motor skills. Sixty-eight percent of the sample met ICD-10 criteria for AS, while 25% fulfilled the diagnostic criteria for autism. Implications for the diagnosis of AS are discussed.