Simultaneous treatment of human bronchial epithelial cells with serine and cysteine protease inhibitors prevents severe acute respiratory syndrome coronavirus entry

The type II transmembrane protease TMPRSS2 activates the spike (S) protein of severe acute respiratory syndrome coronavirus (SARS-CoV) on the cell surface following receptor binding during viral entry into cells. In the absence of TMPRSS2, SARS-CoV achieves cell entry via an endosomal pathway in which cathepsin L may play an important role, i.e., the activation of spike protein fusogenicity. This study shows that a commercial serine protease inhibitor (camostat) partially blocked infection by SARS-CoV and human coronavirus NL63 (HCoV-NL63) in HeLa cells expressing the receptor angiotensin-converting enzyme 2 (ACE2) and TMPRSS2. Simultaneous treatment of the cells with camostat and EST [(23,25)trans-epoxysuccinyl-L-leucylamindo-3-methylbutane ethyl ester], a cathepsin inhibitor, efficiently prevented both cell entry and the multistep growth of SARS-CoV in human Calu-3 airway epithelial cells. This efficient inhibition could be attributed to the dual blockade of entry from the cell surface and through the endosomal pathway. These observations suggest camostat as a candidate antiviral drug to prevent or depress TMPRSS2-dependent infection by SARS-CoV.     

L’échographie-Doppler obstétricale dans la lutte contre les complications materno-fœtales de l’accouchement en salle de travail

ObjectiveTo demonstrate the role of obstetric Doppler ultrasound in reducing the rate of maternal-fetal complications in childbirth.Patients and methodsCase-control study lasting 12 months carried out at the regional hospital center in Yamoussoukro (Ivory Coast). It involved 204 parturients who had a “complicated delivery”. We have divided them into two groups with one group of cases, consisting of 151 parturients who did not have obstetric ultrasound and a group of controls, consisting of 53 parturients who had an obstetric ultrasound during labor. We studied the occurrence of maternal and neonatal complications in the two groups.ResultsDuring the study period, 1182 vaginal deliveries were made. Of these, 204 were complicated (17.3%). Three maternal deaths and 12 cases of uterine rupture were observed in the case group against none maternal complication in the control group. Thirty-eight cases of stillbirth against zero in controls, 69 cases of neonatal brain injury cases against three among controls were evidenced. The causes of complications were dominated by the obstruction (21 cases) followed by abruptio placentae (eight cases) in the mother. Fetal distress (69 cases) followed by the circular of umbilical cord (48 cases) was the dominant causes in fetus.ConclusionComplicated deliveries represent over a quarter of births in Ivory Coast. Most complications can be avoided by an ultrasound exploration of all new mothers in the labor ward.     

Notch, epidermal growth factor receptor, and beta1-integrin pathways are coordinated in neural stem cells

Notch1 and beta1-integrins are cell surface receptors involved in the recognition of the niche that surrounds stem cells through cell-cell and cell-extracellular matrix interactions, respectively. Notch1 is also involved in the control of cell fate choices in the developing central nervous system (Lewis, J. (1998) Semin. Cell Dev. Biol. 9, 583-589). Here we report that Notch and beta1-integrins are co-expressed and that these proteins cooperate with the epidermal growth factor receptor in neural progenitors. We describe data that suggests that beta1-integrins may affect Notch signaling through 1) physical interaction (sequestration) of the Notch intracellular domain fragment by the cytoplasmic tail of the beta1-integrin and 2) affecting trafficking of the Notch intracellular domain via caveolin-mediated mechanisms. Our findings suggest that caveolin 1-containing lipid rafts play a role in the coordination and coupling of beta1-integrin, Notch1, and tyrosine kinase receptor signaling pathways. We speculate that this will require the presence of the adequate beta1-activating extracellular matrix or growth factors in restricted regions of the central nervous system and namely in neurogenic niches.     

Metabolic response to exogenous ethanol in yeast: an in vivo NMR and mathematical modelling approach

The understanding of the metabolic behaviour of complex systems such as eukaryotic cells needs the development of new approaches that are able to deal with the complexity due to a large number of interactions within the system. In this paper, we applied an approach based on the combined use of in vivo NMR experiments and mathematical modelling in order to analyze the metabolic response to ethanol stress in a wild-strain of Saccharomyces cerevisiae. Considering the cellular metabolic processes resulting from activation, inhibition, and feed-back activities, we developed a model able to describe the modulation of the whole system induced by an external stress due to increasing concentrations of exogenous ethanol. This approach was able to interpret the experimental results in terms of metabolic response to exogenous ethanol in the yeast. The robustness and flexibility of the model enables it to work correctly at different initial exogenous ethanol concentrations.     

Analysing Population Numbers of the House Sparrow in the Netherlands With a Matrix Model and Suggestions for Conservation Measures

The House Sparrow (Passer domesticus), formerly a common bird species, has shown a rapid decline in Western Europe over recent decades. In The Netherlands, its decline is apparent from 1990 onwards. Many causes for this decline have been suggested that all decrease the vital rates, i.e. survival and reproduction, but their actual impact remains unknown. Although the House Sparrow has been dominant in The Netherlands, data on life history characteristics for this bird species are scarce: data on reproduction are non-existent, and here we first present survival estimates based on live encounters and dead recoveries of marked individuals over the period 1976–2003, 14 years before and 14 years during the decline, reported to the Dutch Ringing Centre. We show that there is an indication that both juvenile and adult survival are lower during the period of decline. Secondly, to be able to analyse the relative impact of changes in the vital rates, we formulated a general matrix model based on a range of survival values between zero and one with a step size of 0.01 (both juvenile and adult yearly survival) and a range of realistic reproduction values (one, three or five fledglings per pair per year). With the matrix model, we calculated the finite rate of population change (λ) and applied elasticity analysis. To diagnose the cause of the decline in the Dutch House Sparrow, we parameterised the model with estimates of survival values before and during the decline and present the resulting λ. With the survival estimates from the declining period, λ < 1 only if reproduction is relatively low. We discuss this result within the light of available literature data on survival in the House Sparrow. Finally, we evaluate which of the suggested causes of population decline should be reversed to mitigate the decline and how this can be achieved.     

Functional expression of the maize mitochondrial URF13 down-regulates galactose-induced GAL1 gene expression in Saccharomyces cerevisiae

Genes for the enzymes that metabolize galactose in Saccharomyces cerevisiae are strongly induced by galactose and tightly repressed by glucose. Because glucose also represses mitochondrial activity, we examined if derepression of the GAL1 galactokinase gene requires physiologically active mitochondria. The effect of mitochondria on the expression of GAL1 was analyzed by a novel approach in which the activity of the organelles was altered by functional expression of URF13, a mitochondrial protein unique to the Texas-type cytoplasmic male sterility phenotype in maize. Mitochondrial targeting and functional expression of the URF13 protein in yeast result in a decrease of the mitochondrial membrane potential similar to those observed in cells treated with mitochondrial inhibitors such as antimycin A or sodium azide. Activation of URF13 in galactose-induced cells results in the inhibition of GAL1 expression in the absence of repressing concentrations of glucose. Our data reveal the existence of a regulatory pathway that connects the derepression of the GAL1 gene with mitochondrial activity.