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The authors made a comparative study of red cell enzyme glycolysis in man and in two species of Lagomorphae, the pika and the rabbit. The activities of the 12 enzymes of Embden-Meyerhoff pathway and of the two dehydrogenases of pentose shunt (glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase) were determined. Phosphoglycerate kinase and pyruvate kinase showed quite similar activities in pika erythrocytes and in erythrocytes from human umbilical cord. The levels of these enzymes differed significantly in the pika and in the rabbit. No differences were noted between pyruvate kinases from the rabbit and the neonatal man. The other activities gave values either identical to those found in the adult man or intermediate between the adult and the neonatal man. In the rabbit the levels of glycolitic enzymes were generally lower than in the pika except for lactate dehydrogenase and glycose-6-phosphate dehydrogenase. Some characteristics of erythrocyte metabolism specific to the pika may account for the differences observed in this species. The influence of red cell age cannot explain the variations observed for no significant reticulocytosis was observed in the circulating blood. The percentages found in the pika and the rabbit were essentially identical at determination.
Comparative Study of Erythrocyte Glycolytic Enzymes in Man and in Two Species of Lagomorphae
A. Puget and Christine Gouarderes
AIM: To assess, in a routine practice setting, the sustained virologic response (SVR) to telaprevir (TPV) or boceprevir (BOC) in hepatitis C virus (HCV) null-responders or relapsers with severe liver fibrosis.
METHODS: One hundred twenty-five patients were treated prospectively for 48 wk with TPV or BOC + pegylated-interferon (peg-INF) α2a + ribavirin (PR) according to standard treatment schedules without randomization. These patients were treated in routine practice settings in 10 public or private health care centers, and the data were prospectively collected. Only patients with severe liver fibrosis (Metavir scores of F3 or F4 upon liver biopsy or liver stiffness assessed by elastography), genotype 1 HCV and who were null-responders or relapsers to prior PR combination therapy were included in this study.
RESULTS: The Metavir fibrosis scores were F3 in 35 (28%) and F4 in 90 (72%) of the patients. In total, 62.9% of the patients were null-responders and 37.1% relapsers to the previous PR therapy. The overall SVR rate at 24 wk post-treatment withdrawal was 59.8%. The SVR was 65.9% in the TPV group and 44.1% in the BOC group. Independent predictive factors of an SVR included a response to previous treatment, relapsers vs null-responders [OR = 3.9; (1.4, 10.6), P = 0.0084], a rapid virological response (RVR) [OR 6.9 (2.6, 18.2), P = 0.001] and liver stiffness lower than 21.3 kPa [OR = 8.2 (2.3, 29.5), P = 0.001]. During treatment, 63 patients (50.8%) had at least one severe adverse event (SAE) of grade 3 or 4. A multivariate analysis identified two factors associated with SAEs: female gender [OR = 2.4 (1.1, 5.6), P = 0.037] and a platelet count below 150 × 103/ mm3 [OR = 5.3 (2.3, 12.4), P ≤ 0.001].
CONCLUSION: More than half of these difficult-to-treat patients achieved an SVR and had SAEs in an actual practice setting. The SVR rate was influenced by the response to previous PR treatment, the RVR and liver stiffness.
Hepatitis C virus, Hepatitis C, Antiviral therapy, Protease inhibitors, Fibroscan, Liver stiffness, Cirrhosis, Boceprevir, Telaprevir, Ribavirin
Telaprevir- and boceprevir-based tritherapies in real practice for F3-F4 pretreated hepatitis C virus patients
Delphine Bonnet, Matthieu Guivarch, Emilie Berard, Jean-Marc Combis, Andre Jean Remy, Andre Glibert, Jean-Louis Payen, Sophie Metivier, Karl Barange, Herve Desmorat, Anaïs Palacin, Florence Nicot, Florence Abravanel, and Laurent Alric
2014 Sep 27
The evolution of the full repertoire of proteins encoded in a given genome is mostly driven by gene duplications, deletions, and sequence modifications of existing proteins. Indirect information about relative rates and other intrinsic parameters of these three basic processes is contained in the proteome-wide distribution of sequence identities of pairs of paralogous proteins.
We introduce a simple mathematical framework based on a stochastic birth-and-death model that allows one to extract some of this information and apply it to the set of all pairs of paralogous proteins in H. pylori, E. coli, S. cerevisiae, C. elegans, D. melanogaster, and H. sapiens. It was found that the histogram of sequence identities p generated by an all-to-all alignment of all protein sequences encoded in a genome is well fitted with a power-law form ~ p-γ with the value of the exponent γ around 4 for the majority of organisms used in this study. This implies that the intra-protein variability of substitution rates is best described by the Gamma-distribution with the exponent α ≈ 0.33. Different features of the shape of such histograms allow us to quantify the ratio between the genome-wide average deletion/duplication rates and the amino-acid substitution rate.
We separately measure the short-term (“raw”) duplication and deletion rates r∗dup, r∗del which include gene copies that will be removed soon after the duplication event and their dramatically reduced long-term counterparts rdup, rdel. High deletion rate among recently duplicated proteins is consistent with a scenario in which they didn’t have enough time to significantly change their functional roles and thus are to a large degree disposable. Systematic trends of each of the four duplication/deletion rates with the total number of genes in the genome were analyzed. All but the deletion rate of recent duplicates r∗del were shown to systematically increase with Ngenes. Abnormally flat shapes of sequence identity histograms observed for yeast and human are consistent with lineages leading to these organisms undergoing one or more whole-genome duplications. This interpretation is corroborated by our analysis of the genome of Paramecium tetraurelia where the p-4 profile of the histogram is gradually restored by the successive removal of paralogs generated in its four known whole-genome duplication events.
Parameters of proteome evolution from histograms of amino-acid sequence identities of paralogous proteins
Jacob Bock Axelsen,1,2 Koon-Kiu Yan,2,3 and Sergei Maslovcorresponding author2,3