Interaction between cystatin-derived peptides and papain

The interaction between papain and synthetic peptides which tentatively mimic cystatin surfaces was investigated both enzymatically and structurally. Measurements of dissociation equilibrium constants for the interaction of papain with these peptides modified by successive deletions or substitutions demonstrated that the QVVAG segment, which is highly conserved throughout members of the cystatin superfamily, is essential for the interaction. The glycylcontaining (N-terminal) fragments and PW-containing (C-terminal) fragments were found to be of lesser importance, since each could be deleted without significantly modifying the interaction. These fragments improved the stability of the interacting QVVAG region, which appeared to be substrate-like in all peptides tested, as it was cleaved at the A-G bond upon peptide-papain interaction. Replacement of the A residue at the scissile bond of the QVVAG by a blocked cysteinyl residue reduced the rate of cleavage of the susceptible bond and therefore shifted the resulting peptide from a substrate to an inhibitor. Derivatization of this substituted peptide at its N- and C-terminal ends by fluoresceinyl groups resulted in a dramatic decrease in theK _i to 0.5 µM. This improvement in the inhibitory properties of the substituted and derivatized peptides was correlated with structural changes as analyzed by molecular dynamic calculations. The results were compared to those proposed for the mechanism of inhibition by natural inhibitors of the cystatin superfamily.     

Genetic Screens Identify Host Factors for SARS-CoV-2 and Common Cold Coronaviruses

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Osteopromotion of Biphasic Calcium Phosphate granules in critical size defects after osteonecrosis induced by focal heating insults

Heat-induced osteonecrosis represents a simple, rapid, and inexpensive method for reproducing the effects of bone disease. In the present study, we employed this technique to induce osteonecrosis in femoral defects in rabbits and assessed the efficacy of treatment using Biphasic Calcium Phosphate (BCP) granules (MBCP+?, Biomatlante SA). After 3 weeks, the osteopromotion effects of BCP granules could be statistically proven (P < 0.05) through image analysis of newly formed bone in osteonecrosed sites containing BCP granules when compared to empty control sites. Increasing mature and woven bone presence was observed after 6 and 12 weeks, forming new trabeculae in necrosed site. Significant statistical differences were evidenced at each time between empty necrosed and filled necrosed defects in terms of new bone volume.     

A nuclear magnetic resonance study of the interactions of antimalarial drugs with porphyrins

Haematins (hydroxyferriprotoporphyrin IX) constitute a possible receptor for antimalarial drugs such as chloroquine or quinine. This paper reports the study of the interactions of these two molecules with two tetrapyrrole (haematin and uroporphyrin I) by 1H-NMR spectroscopy. This method provided us with the geometry of the interactions in aqueous medium. The interaction consists of a close stacking of the porphyrin ring and the quinoleine moiety of the drugs. Using a porphyrin ring current model it was possible to reach the spatial relationships of the interacting species. It was concluded that hydrophobic forces play a key role in the interaction. The porphyrin plane can accommodate wide structural variations of the interacting species, leading to a weak specificity. The consequences on the mode of action of antimalarial drugs are discussed.     

Development of gastric sensitivity to histamine in the rat

Sensitivity of the developing rat stomach to histamine (HA) was examined on isolated gastric mucosae of rats of various ages from the fetal to adult periods. Spontaneous acid secretion in mu eq/h.cm2 occurred at all the ages studied, at a basal rate of 0.45 +/- 0.07 in fetuses to 0.22 +/- 0.03 (day 5), 0.11 +/- 0.04 (day 10), 0.12 +/- 0.04 (day 12), 0.22 +/- 0.08 (day 16) and 0.33 +/- 0.04 (adults). In the fetal rats as in the adults, marked responses to respectively 10(-5) and 10(-4) M HA were demonstrated. The H2-receptor antagonist cimetidine diminished HA-induced secretion by 66 and 57% in fetuses and adults respectively. Between these two stages (from days 5 to 12), basal secretion and the response to HA dropped significantly. On day 21 of gestation, as well as on the critical days 5 and 12 after parturition, db-cAMP (10(-4) M) caused maximal stimulation of acid secretion. These results indicate that the development of responsiveness to HA in the rat is biphasic. They suggest that after birth, the H2-receptor adenylate cyclase system undergoes major modifications which might lead to the complete lack of responsiveness to HA by day 12.     

Identifying common prognostic factors in genomic cancer studies: A novel index for censored outcomes

Background  

With the growing number of public repositories for high-throughput genomic data, it is of great interest to combine the results produced by independent research groups. Such a combination allows the identification of common genomic factors across multiple cancer types and provides new insights into the disease process. In the framework of the proportional hazards model, classical procedures, which consist of ranking genes according to the estimated hazard ratio or the p-value obtained from a test statistic of no association between survival and gene expression level, are not suitable for gene selection across multiple genomic datasets with different sample sizes. We propose a novel index for identifying genes with a common effect across heterogeneous genomic studies designed to remain stable whatever the sample size and which has a straightforward interpretation in terms of the percentage of separability between patients according to their survival times and gene expression measurements.     

Rhesus macaques build new social connections after a natural disaster

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Alpha Reactivity to Complex Sounds Differs during REM Sleep and Wakefulness

We aimed at better understanding the brain mechanisms involved in the processing of alerting meaningful sounds during sleep, investigating alpha activity. During EEG acquisition, subjects were presented with a passive auditory oddball paradigm including rare complex sounds called Novels (the own first name - OWN, and an unfamiliar first name - OTHER) while they were watching a silent movie in the evening or sleeping at night. During the experimental night, the subjects’ quality of sleep was generally preserved. During wakefulness, the decrease in alpha power (8–12 Hz) induced by Novels was significantly larger for OWN than for OTHER at parietal electrodes, between 600 and 900 ms after stimulus onset. Conversely, during REM sleep, Novels induced an increase in alpha power (from 0 to 1200 ms at all electrodes), significantly larger for OWN than for OTHER at several parietal electrodes between 700 and 1200 ms after stimulus onset. These results show that complex sounds have a different effect on the alpha power during wakefulness (decrease) and during REM sleep (increase) and that OWN induce a specific effect in these two states. The increased alpha power induced by Novels during REM sleep may 1) correspond to a short and transient increase in arousal; in this case, our study provides an objective measure of the greater arousing power of OWN over OTHER, 2) indicate a cortical inhibition associated with sleep protection. These results suggest that alpha modulation could participate in the selection of stimuli to be further processed during sleep.