CYCLOSPORIN A INHIBITS THE IN VIVO PRODUCTION OF INTERLEUKIN-1β AND TUMOUR NECROSIS FACTOR α, BUT NOT INTERLEUKIN-6, BY A T-CELL-INDEPENDENT MECHANISM

The effect of cyclosporin A (CsA) on cytokine production in the tissue chamber model of acute inflammation was investigated. CsA caused a dose-related inhibition of interleukin 1β (IL-1β) production in both normal and athymic mice, confirming earlier conclusions that this effect is not T cell dependent (ED₅₀s 40 and 53 mg/kg p.o., respectively).Tumour necrosis factor alpha (TNF-α) levels were similarly affected with ED₅₀s of 40 and 58 mg/kg p.o. for normal and athymic mice, respectively. By contrast, CsA inhibited interleukin 6 (IL-6) production only in normal mice (ED₅₀27 mg/kg p.o.)Differences in the absolute production of the three cytokines in normal and athymic mice were also noted. IL-1β and IL-6 levels were two-fold higher in athymic mice, while for TNF-α, there was no difference between the two groups.The present findings support the authors' original hypothesis, that the inhibitory mechanism of CsA on IL-1β is not mediated via T cells. The same mechanism also seems responsible for the inhibition of TNF-α production, but not for IL-6, where inhibition by CsA appears to require the presence of T cells.     

EARLY DEVONIAN FISHES FROM GUIJIATUN AND XUJIACHONG FORMATIONS OF QUJING,YUNNAN,AND RELATED BIOSTRATIGRAPHIC PROBLEMS

Pale0nt0IogicStudiesSubclassGaleaspidaHalsteadTarl0,l9670rderHuanana8piformesJanvier,l975FamilyGantar0stra8pidaeWangetWang,l992GenusCantarostraspisWangetWang,l992CQntarostra8pisgeniWangetWang,l992(Fig.l3Pl-II,4-5)1992,Gantarostraspisgeni,Wang,J.Q.etWang,N.Z.,Fig-l,Pl.l.HolotypeAdorsalshieldV9758,LowerDevonianPosongchongF0rmation,Gu-mu,Wenshandistrict,Yunnan-ReferredspeeimensAdorsalshieldVlO494.1;arostra1pr0cessV1O494.2.Loca1ityandh0riz0nXujiach0ng,Xishan,Qujing,Yunnan,Lowe…     

ARE CELL KINETIC DATA RELEVANT FOR THE DESIGN OF TUMOUR CHEMOTHERAPY SCHEDULES?*

The data on the importance of the application of information on cell kinetics for the success of tumour chemotherapy are critically reviewed. It is concluded that the data on cell sensitivity to drugs as affected by cell kinetic variables are as yet insufficient to permit the prediction of optimal dosage schedules for tumour therapy. More information is needed on differential responses and differential kinetic features of normal and malignant tissues. Optimistic views of cell kinetics as an easy answer to the problems of drug dosage schedule design are unjustified, but so is the disenchantment with cell kinetics as a fruitful approach. Much further work, especially on the drug sensitivity of cellular compartments in slow growing tumours, is needed before a complete evaluation of this tool is possible.     

DNA Polymerase β Ribonucleotide Discrimination: INSERTION,MISINSERTION, EXTENSION,AND CODING*

DNA polymerases must select nucleotides that preserve Watson-Crick base pairing rules and choose substrates with the correct (deoxyribose) sugar. Sugar discrimination represents a great challenge because ribonucleotide triphosphates are present at much higher cellular concentrations than their deoxy-counterparts. Although DNA polymerases discriminate against ribonucleotides, many therapeutic nucleotide analogs that target polymerases have sugar modifications, and their efficacy depends on their ability to be incorporated into DNA. Here, we investigate the ability of DNA polymerase β to utilize nucleotides with modified sugars. DNA polymerase β readily inserts dideoxynucleoside triphosphates but inserts ribonucleotides nearly 4 orders of magnitude less efficiently than natural deoxynucleotides. The efficiency of ribonucleotide insertion is similar to that reported for other DNA polymerases. The poor polymerase-dependent insertion represents a key step in discriminating against ribonucleotides because, once inserted, a ribonucleotide is easily extended. Likewise, a templating ribonucleotide has little effect on insertion efficiency or fidelity. In contrast to insertion and extension of a ribonucleotide, the chemotherapeutic drug arabinofuranosylcytosine triphosphate is efficiently inserted but poorly extended. These results suggest that the sugar pucker at the primer terminus plays a crucial role in DNA synthesis; a 3′-endo sugar pucker facilitates nucleotide insertion, whereas a 2′-endo conformation inhibits insertion.     

DIURNAL,AGE, AND IMMUNE REGULATION OF INTERLEUKIN-1β AND INTERLEUKIN-1 TYPE 1 RECEPTOR IN THE MOUSE SUPRACHIASMATIC NUCLEUS

Circadian clocks serve to impose a near-24-h temporal architecture on an organism's physiology, metabolism, and behavior. In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus functions as the master circadian pacemaker. There is growing evidence that immunomodulators, such as cytokines, may impinge on circadian timekeeping. We examined whether there is endogenous expression of the proinflammatory cytokine interleukin-1β (IL-1β) and its signaling receptor IL-1R1 in the SCN of young and older mice across the diurnal cycle. We found expression of both IL-1β and IL-1R1 in the young SCN, although only IL-1R1 displayed temporal regulation. In the older SCN, levels of IL-1β were expressed at lower levels than in the young SCN, and IL-1R1 did not vary across the 24?h. We also report age-related day-night variation of IL-1β and IL-1R1 in the paraventricular nucleus (PVN) of the hypothalamus. Further, we examined the effect of peripheral immune challenge on IL-1β and IL-1R1 in the SCN. We found that IL-1β immunoreactivity was not altered 6 or 24?h after a septic dose of lipopolysaccharide (LPS; 5?mg/kg), whereas IL-1R1 was significantly up-regulated in the SCN both 6 and 24?h after LPS. We also demonstrate cellular activation in the SCN 24?h following LPS treatment, as evidenced by increased c-Fos and p65-NF-κB (nuclear factor kappa B) expression. Our results indicate that IL-1β and its associated signaling system may play a role in mediating the response of the circadian timing system to immune challenge as well as potentially contributing to the basal functioning of the SCN clock. (Author correspondence: andrew.coogan@nuim.ie)     

CARBONIFEROUS-PERMIAN BOUNDARY BEDS AND FUSULINID ZONES AT XIAODUSHAN, GUANGNAN, EASTERN YUNNAN

The Xiaodushan section is situated at about 5 km from the Babao village in Guangnan County in eastern Yunnan. In this section, the stratigraphic suecession from Lower Carboniferous to Middle Permian is continuous and ex-