Hepatitis C virus proteins Dubuisson, Jean
World journal of gastroenterology,
05/2007, Volume:
13, Issue:
17
Journal Article
Open access
Hepatitis C virus (HCV) encodes a single polyprotein, which is processed by cellular and viral proteases to generate 10 polypeptides. The HCV genome also contains an overlapping +1 reading frame that ...may lead to the synthesis of an additional protein. Until recently, studies of HCV have been hampered by the lack of a productive cell culture system. Since the identification of HCV genome approximately 17 years ago, structural, biochemical and biological information on HCV proteins has mainly been obtained with proteins produced by heterologous expression systems. In addition, some functional studies have also been confirmed with replicon systems or with retroviral particles pseudotyped with HCV envelope glycoproteins. The data that have accumulated on HCV proteins begin to provide a framework for understanding the molecular mechanisms involved in the major steps of HCV life cycle. Moreover, the knowledge accumulated on HCV proteins is also leading to the development of antiviral drugs among which some are showing promising results in early-phase clinical trials. This review summarizes the current knowledge on the functions and biochemical features of HCV proteins.
Burch colposuspension Veit‐Rubin, Nikolaus; Dubuisson, Jean; Ford, Abigail ...
Neurourology and urodynamics,
February 2019, Volume:
38, Issue:
2
Journal Article
Peer reviewed
Open access
Aims
To evaluate the historic and pathophysiologic issues which led to the development of Burch colposuspension, to describe anatomic and technical aspects of the operation and to provide an update ...on current evidence.
Methods
We have performed a focused literature review and have searched the current available literature about historic dimension, technical descriptions, and efficacy of Burch colposuspension.
Results
Burch colposuspension, performed either by an open or a laparoscopic approach, is an effective surgical treatment for stress urinary incontinence.
Conclusions
In current recommendations, Burch colposuspension remains an option for secondary treatment. Because midurethral slings have recently become under scrutiny, it may return as a first‐line treatment procedure. Both open and laparoscopic Burch colposuspension should therefore nowadays be provided in fellowship programs worldwide.
Summary Hepatitis C virus (HCV) is an important human pathogen that causes hepatitis, liver cirrhosis and hepatocellular carcinoma. It imposes a serious problem to public health in the world as the ...population of chronically infected HCV patients who are at risk of progressive liver disease is projected to increase significantly in the next decades. However, the arrival of new antiviral molecules is progressively changing the landscape of hepatitis C treatment. The search for new anti-HCV therapies has also been a driving force to better understand how HCV interacts with its host, and major progresses have been made on the various steps of the HCV life cycle. Here, we review the most recent advances in the fast growing knowledge on HCV life cycle and interaction with host factors and pathways.
Hepatitis C virus (HCV) envelope glycoprotein heterodimer, E1E2, plays an essential role in virus entry and assembly. Furthermore, due to their exposure at the surface of the virion, these proteins ...are the major targets of anti-HCV neutralizing antibodies. Their ectodomain are heavily glycosylated with up to 5 sites on E1 and up to 11 sites on E2 modified by N-linked glycans. Thus, one-third of the molecular mass of E1E2 heterodimer corresponds to glycans. Despite the high sequence variability of E1 and E2, N-glycosylation sites of these proteins are generally conserved among the seven major HCV genotypes. N-glycans have been shown to be involved in E1E2 folding and modulate different functions of the envelope glycoproteins. Indeed, site-directed mutagenesis studies have shown that specific glycans are needed for virion assembly and infectivity. They can notably affect envelope protein entry functions by modulating their affinity for HCV receptors and their fusion activity. Importantly, glycans have also been shown to play a key role in immune evasion by masking antigenic sites targeted by neutralizing antibodies. It is well known that the high mutational rate of HCV polymerase facilitates the appearance of neutralization resistant mutants, and occurrence of mutations leading to glycan shifting is one of the mechanisms used by this virus to escape host humoral immune response. As a consequence of the importance of the glycan shield for HCV immune evasion, the deletion of N-glycans also leads to an increase in E1E2 immunogenicity and can induce a more potent antibody response against HCV.
Introduction and hypothesis
Sacropexy is considered the gold standard for the treatment of pelvic organ prolapse (POP) although dissection of the promontory may be challenging, particularly in obese ...women. Laparoscopic lateral suspension with mesh (LLS) could be an alternative.
Methods
LLS provides lateral attachment by fibrosis of a vesicovaginal mesh. Clinical evaluation was performed at 1 year using the simplified POP quantification system (POP-Q). Primary outcomes were objective and subjective cure at 1 year. After a mean of 7.2 years the rates of reoperation and complications were assessed as secondary outcomes. Patient satisfaction was evaluated by telephone interview using a ten-point-scale and the PGI-I scale. Factors predicting satisfaction were determined by logistic regression analysis.
Results
A total of 417 patients were treated between 2003 and 2011. At 1 year 78.4% of patients were asymptomatic and anatomic success rates were 91.6% for the anterior compartment, 93.6% for the apical compartment and 85.3% for the posterior compartment. The complication rate of Clavien-Dindo grade III or higher was 2.2%. The mesh exposure rate was 4.3% and the reoperation rate was 7.3%. Of the 417 patients, 214 participated in the telephone interview. Over 85% rated their situation as improved and satisfaction was associated with the absence of concomitant hysterectomy.
Conclusions
LLS is a safe technique with promising results in terms of a composite outcome, low complication rates and high long-term patient satisfaction. However, a randomized controlled trial is needed to establish the technique as an alternative to sacropexy in the treatment of POP in obese and high morbidity patients.
Hepatitis C virus (HCV) causes chronic infection in almost 2% of the world's population. If untreated, chronic carriers can develop severe liver disease including fibrosis, cirrhosis and ...hepatocellular carcinoma. Until recently, hepatitis C was treated with a combination of pegylated interferon and ribavirin, a treatment which was only partially effective and was plagued with side effects. In 2011 two inhibitors of the virally encoded NS3/4 protease have become part of standard therapy, which have improved treatment rates but can exacerbate the problematic side effects. While the addition of these first directly acting antivirals (DAAs) marks a milestone in anti-HCV therapy, new and improved combinations of drugs are desperately needed. New generations of drugs will have to address genetic variability of HCV and issues of viral resistance. Furthermore, combination therapies have to be tailored to effectively cure patient populations that have traditionally been hardest to treat, including patients with cirrhosis, those receiving liver transplants and individuals who are co-infected with HIV or hepatitis B virus. Since the discovery of HCV a plethora of experimental tools have been developed which enabled detailed analysis of various aspects of the viral life cycle and the interaction of HCV with its human host. Such studies have revealed a growing list of targets for therapeutic intervention, some of which will be discussed in this review.
Introduction and hypothesis
Changes in the psychological value of reproductive organs have led to a growing interest in uterine-preserving surgery for pelvic organ prolapse (POP). Sacral hysteropexy ...is considered as gold standard, although dissection of the promontory may be challenging. We show a video and present a report on a series of patients operated by laparoscopic lateral suspension with mesh as an alternative.
Methods
Clinical evaluation was performed using the simplified Pelvic Organ Prolapse Quantification System (POP-Q). Primary outcomes were subjective and objective cure; secondary outcomes were rates for reoperation and complications. We assessed patient’s satisfaction in a telephone interview using a visual analogue scale and the Patient Global Impression of Improvement Scale (PGI-I) scale.
Results
Two hundred and fifty-four patients were treated between 2004 and 2011 with a median follow-up of 7.5 years. At 1 year 82.7 % of patients were asymptomatic, and anatomic success rates were 88.2 % for the anterior, 86.1 % for the apical and 80.8 % for the posterior compartment; 1.2 % had mesh exposure, and the reoperation rate was 7.4 %. More than 80 % of patients were highly satisfied with the outcome.
Conclusions
Uterine-preserving laparoscopic lateral suspension with mesh is a safe technique with promising results and low complication rates. It may be an alternative to sacral hysteropexy for high-morbidity patients.
A better understanding of the anti-SARS-CoV-2 immune response is necessary to finely evaluate commercial serological assays but also to predict protection against reinfection and to help the ...development of vaccines. For this reason, we monitored the anti-SARS-CoV-2 antibody response in infected patients. In order to assess the time of seroconversion, we used 151 samples from 30 COVID-19 inpatients and monitored the detection kinetics of anti-S1, anti-S2, anti-RBD and anti-N antibodies with in-house ELISAs. We observed that specific antibodies were detectable in all inpatients 2 weeks post-symptom onset and that the detection of the SARS-CoV-2 Nucleocapsid and RBD was more sensitive than the detection of the S1 or S2 subunits. Using retroviral particles pseudotyped with the spike of the SARS-CoV-2, we also monitored the presence of neutralizing antibodies in these samples as well as 25 samples from asymptomatic individuals that were shown SARS-CoV-2 seropositive using commercial serological tests. Neutralizing antibodies reached a plateau 2 weeks post-symptom onset and then declined in the majority of inpatients but they were undetectable in 56% of asymptomatic patients. Our results indicate that the SARS-CoV-2 does not induce a prolonged neutralizing antibody response. They also suggest that induction of neutralizing antibodies is not the only strategy to adopt for the development of a vaccine. Finally, they imply that anti-SARS-CoV-2 neutralizing antibodies should be titrated to optimize convalescent plasma therapy.
Epiphytism has evolved repeatedly in plants and has resulted in a considerable number of species with original characteristics. Because water supply is generally erratic compared to that in soils, ...succulent forms in particular are widespread in epiphytic species. However, succulent organs also exist in terrestrial plants, and the question of the concomitant evolution of epiphytism and succulence has received little attention, not even in the epidendroid orchids, which account for 67.6 % of vascular epiphytes.
We built a new time-calibrated phylogenetic tree of Epidendroideae with 203 genera treated in genus Orchidacearum, from which we reconstructed the evolution of epiphytism as well as traits related to water scarcity (stem and leaf succulence and the number of velamen layers), while testing for the correlated evolution between the two. Furthermore, we estimated the ancestral geographical ranges to evaluate the palaeoclimatic context in which epiphytism evolved.
Epiphytism evolved at least three times: 39.0 million years ago (Mya) in the common ancestor of the Malaxideae and Cymbidieae that probably ranged from the Neotropics to Southeast Asia and Australia, 11.5 Mya in the Arethuseae in Southeast Asia and Australia, and 7.1 Mya in the neotropical Sobralieae, and it was notably lost in the Malaxidiinae, Collabieae, Calypsoeae, Bletiinae and Eulophiinae. Stem succulence is inferred to have evolved once, in a terrestrial ancestor at least 4.1 Mya before the emergence of epiphytic lineages. If lost, stem succulence was almost systematically replaced by leaf succulence in epiphytic lineages.
Epiphytism may have evolved in seasonally dry forests during the Eocene climatic cooling, among stem-succulent terrestrial orchids. Our results suggest that the emergence of stem succulence in early epidendroids was a key innovation in the evolution of epiphytism, facilitating the colonization of epiphytic environments that later led to the greatest diversification of epiphytic orchids.
Hepatitis E virus (HEV) infection is a major cause of acute hepatitis worldwide. Approximately 2 billion people live in areas endemic for HEV and are at risk of infection. The HEV genome encodes 3 ...proteins, including the ORF2 capsid protein. Detailed analyses of the HEV life cycle has been hampered by the lack of an efficient viral culture system.
We performed studies with gt3 HEV cell culture–produced particles and patient blood and stool samples. Samples were fractionated on iodixanol gradients and cushions. Infectivity assays were performed in vitro and in human liver chimeric mice. Proteins were analyzed by biochemical and proteomic approaches. Infectious particles were analyzed by transmission electron microscopy. HEV antigen levels were measured with the Wantaï enzyme-linked immunosorbent assay.
We developed an efficient cell culture system and isolated HEV particles that were infectious in vitro and in vivo. Using transmission electron microscopy, we defined the ultrastructure of HEV cell culture–produced particles and particles from patient sera and stool samples. We also identified the precise sequence of the infectious particle-associated ORF2 capsid protein. In cultured cells and in samples from patients, HEV produced 3 forms of the ORF2 capsid protein: infectious/intracellular ORF2 (ORF2i), glycosylated ORF2 (ORF2g), and cleaved ORF2 (ORF2c). The ORF2i protein associated with infectious particles, whereas the ORF2g and ORF2c proteins were massively secreted glycoproteins not associated with infectious particles. ORF2g and ORF2c were the most abundant antigens detected in sera from patients.
We developed a cell culture system and characterized HEV particles; we identified 3 ORF2 capsid proteins (ORF2i, ORF2g, and ORFc). These findings will advance our understanding of the HEV life cycle and improve diagnosis.
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