Analysis of diversity of hepatitis C virus glycoproteins E1 and E2

Hepatitis C Virus (HCV) exists as a population of sequence variants that evolves during infection adapting to host pressures. The main targets for the immune response are the envelope glycoproteins E1 and E2, which also mediate viral cell entry. The first hypervariable region (HVR1) of E2, previously implicated in the outcome of acute infection, has been a focus of many studies. However more broadly neutralising antibodies tend to target epitopes outside this region, yet evolution of full length E1E2 heterodimer is poorly understood. The HCV transmission and window period as well as seroconversion are the evolutionary events shaping primary infection hence influencing outcome of acute infection. However, due to the asymptomatic character of the early phases of HCV infection, evolutionary data describing this interval is still lacking depth. Defining the genetic and phenotypic characteristics of HCV population of sequence variants that establish infection in a new host would aid vaccine and new therapy design. This study aimed to identify patterns of HCV envelope glycoprotein evolution upon transmission and during early phases of disease. We studied this in three settings: experimental transmission of immunocompromised mice by known inoculum; occurrence of horizontal transmission in a haemodialysis unit between hypothesised source and index case individuals; and unrelated cases of acutely infected HCV patients. The single genome amplification (SGA) approach was utilised, which allowed us to accurately assign linkage between substitutions and determine the frequency distribution of E1E2 variants in analysed viral populations. Data from the first experimental setting indicates that a selective sweep occurs upon HCV transmission, with selective amplification of envelope sequence variants that possess fitness advantage at entry level. Molecular determinants associated with this enhanced infectivity have also been identified. In further part of the project we confirmed a horizontal infection in haemodialysis unit with use of phylogenetic methods and suggested revision of current safety guidelines. Analysis of sequences from the last setting showed that indeed HVR1 might not be a good enough indicator of evolutionary events in the acute phase, as linked substitutions occur also outside this region. Seroconversion is associated with increasing population diversity indicating role of antibodies in driving HCV evolution, which is host specific

Analysis of diversity of hepatitis C virus glycoproteins E1 and E2

Hepatitis C Virus (HCV) exists as a population of sequence variants that evolves during infection adapting to host pressures. The main targets for the immune response are the envelope glycoproteins E1 and E2, which also mediate viral cell entry. The first hypervariable region (HVR1) of E2, previously implicated in the outcome of acute infection, has been a focus of many studies. However more broadly neutralising antibodies tend to target epitopes outside this region, yet evolution of full length E1E2 heterodimer is poorly understood. The HCV transmission and window period as well as seroconversion are the evolutionary events shaping primary infection hence influencing outcome of acute infection. However, due to the asymptomatic character of the early phases of HCV infection, evolutionary data describing this interval is still lacking depth. Defining the genetic and phenotypic characteristics of HCV population of sequence variants that establish infection in a new host would aid vaccine and new therapy design. This study aimed to identify patterns of HCV envelope glycoprotein evolution upon transmission and during early phases of disease. We studied this in three settings: experimental transmission of immunocompromised mice by known inoculum; occurrence of horizontal transmission in a haemodialysis unit between hypothesised source and index case individuals; and unrelated cases of acutely infected HCV patients. The single genome amplification (SGA) approach was utilised, which allowed us to accurately assign linkage between substitutions and determine the frequency distribution of E1E2 variants in analysed viral populations. Data from the first experimental setting indicates that a selective sweep occurs upon HCV transmission, with selective amplification of envelope sequence variants that possess fitness advantage at entry level. Molecular determinants associated with this enhanced infectivity have also been identified. In further part of the project we confirmed a horizontal infection in haemodialysis unit with use of phylogenetic methods and suggested revision of current safety guidelines. Analysis of sequences from the last setting showed that indeed HVR1 might not be a good enough indicator of evolutionary events in the acute phase, as linked substitutions occur also outside this region. Seroconversion is associated with increasing population diversity indicating role of antibodies in driving HCV evolution, which is host specific

Six short films

SIX SHORT FILMS 1. SPACE-TIME "SPACE-TIME" was my first experiment in time-lapse and slow motion photography. By double printing these effects, I altered time and space on the screen with these two extremes. The scale of the woman to the landscape is also a part of the reversal of the natural order of big/slow to small/fast. The action is also reversed. 2. TURNPIKE TRIP "Going Down The Road Feeling Bad", the music track for "TURNPIKE TRIP" is competing against my experiment with sound effects just as the effects compete with the animations of Bob Gerhart's fine drawings. I first saw the fifty drawings at the printers being reproduced for Bob's forthcoming book and felt they would be an ideal subject for my first trial in animation. The drawings and continuity were so complete and strong in their arrangements that it left little room for varying his story. Therefore, I can only credit myself with an exercise in sound/picture recording and editing and look forward to having my copy of his book

An International, Web-Based, Prospective Cohort Study to Determine Whether the Use of ACE Inhibitors prior to the Onset of Scleroderma Renal Crisis Is Associated with Worse Outcomes—Methodology and Preliminary Results

Background. To describe the methodology of a study designed to determine whether systemic sclerosis (SSc) patients with incident scleroderma renal crisis (SRC) on angiotensin converting enzyme (ACE) inhibitors prior to the onset of SRC have worse outcomes. Methods. Prospective, international cohort study of SRC subjects identified through an ongoing web-based survey. Every second Friday afternoon, an e-mail was sent to 589 participating physicians to identify new cases of SRC. Death or dialysis at one year after the onset of SRC will be compared in patients exposed or not to ACE inhibitors prior to the onset of SRC. Results. Fifteen months after the start of the survey, we had identified 76 incident cases of SRC. Of these, 66 (87%) had a hypertensive SRC and 10 (13%) a normotensive SRC. Twenty-two percent (22%) of the patients were on an ACE inhibitor immediately prior to the onset of the SRC. To date, we have collected one-year follow-up data on approximately 1/3 of the cohort. Of these, over 50% have died or remain on dialysis at one year. Conclusion. An international, web-based cohort study design is a feasible method of recruiting a substantial number of patients to study an infrequent vascular manifestation of SSc

Mitochondrial DNA changes in pedunculopontine cholinergic neurons in Parkinson’s disease

In Parkinson’s disease (PD), mitochondrial dysfunction associates with nigral dopaminergic neuronal loss. Cholinergic neuronal loss co-occurs, particularly within a brainstem structure, the pedunculopontine nucleus (PPN). We isolated single cholinergic neurons from post-mortem PPNs of aged controls and PD patients. Mitochondrial DNA (mtDNA) copy number and mtDNA deletions were increased significantly in PD patients compared to controls. Furthermore, compared to controls the PD patients had significantly more PPN cholinergic neurons containing mtDNA deletion levels exceeding 60%, a level associated with deleterious effects on oxidative phosphorylation. The current results differ from studies reporting mtDNA depletion in nigral dopaminergic neurons of PD patients

Evolution of Terrestrial Habitat in Manophylax Species (Trichoptera:Apataniidae), with a New Species from Alaska

The genus Manophylax (Trichoptera:Apataniidae) contains 3 species from the Nearctic Region and 3 species from Japan. A 7th species of Manophylax new for science is described and illustrated from Alaska. Habitats of larvae and pupae of the different Manophylax species are either mostly hygropetric or mostly terrestrial. Phylogenetic analysis infers 3 principal species groups occurring in the eastern and western Nearctic and eastern Palearctic Biogeographic Regions. The habitat of the western Nearctic M. annulatus Species Group is mostly hygropetric and that of the eastern Nearctic M. altus and eastern Palearctic M. futabae Species Groups are mostly terrestrial. The phylogeny suggests that the mostly terrestrial habitat evolved through a mostly hygropetric habitat. The phylogeny also implies that the eastern Nearctic and eastern Palearctic species share a more recent common ancestor than they share with the western Nearctic species, a result further supporting a commonly observed historical biogeographic pattern for these regions. Madeophylax Huryn and Wallace is redefined as a subgenus of Manophylax Wiggins, including the species of the M. altus and M. futabae Species Groups. Keys to adult males, females, larvae, and pupae of the 4 North American species of Manophylax are included

Does mitochondrial DNA predispose to neuromyelitis optica (Devic's disease)?

Neuromyelitis optica (NMO), or Devic's disease, is a relapsing demyelinating disease of the central nervous system characterized by optic neuritis and myelitis with distinct clinical, imaging, CSF and serological features (Wingerchuk et al. , 2006). There is increasing evidence that NMO is an antibody-mediated organ-specific autoimmune disease associated with anti-aquaporin 4 antibodies detectable in serum (Lennon et al. , 2004), supported by four recent papers in the same edition of Brain (Matsuoka et al. , 2007; Misu et al. , 2007; Roemer et al. , 2007; Takahashi et al. , 2007) and the accompanying scientific commentary (Compston, 2007). However, it is still not known why the disorder specifically targets the optic nerves and spinal cord. Several siblings with NMO have been reported (McAlpine, 1938; Keegan and Weinshenker, 2000; Yamakawa et al. , 2000), raising the possibility of a genetic predisposition, but no pathogenic mutations have been identified in the AQP4 gene on chromosome 18q11.2-q12.1 (Lu et al. , 1996). NMO has similarities with Leber hereditary optic neuropathy (LHON, MIM 535 000) which is primarily due to mutations of mitochondrial DNA (mtDNA) that disrupt complex I of the respiratory chain (Carelli et al. , 2004). Although the genetic defect in LHON is present in all tissues, the pathology also is strikingly tissue-specific. Most affected individuals develop sub-acute painless visual failure due to focal involvement of both optic nerves (Newman et al. , 1991; Riordan-Eva et al. , 1995), but some also develop a progressive myelopathy, with high signal extending over multiple spinal levels on MR imaging, and the absence of oligoclonal bands in the CSF (Johns et al. , 1991; Jaros et al. , 2007). Tissue-specific susceptibility to mitochondrial dysfunction is thought to explain why the neurodegeneration in LHON only affects specific neuronal

Community based aquaculture in the western Indian Ocean: Challenges and opportunities for developing sustainable coastal livelihoods

The small-fisheries social-ecological system in the western Indian Ocean (WIO) represents a typical social-ecological trap setting where very poor natural resources dependent coastal communities face local and global threats and engage in unsustainable practices of exploiting limited resources. Community-based aquaculture (CBA) has been implemented as an important alternative or supplementary income generating activity for minimizing the overdependence on marine natural resources and promoting biodiversity conservation. Despite its proliferation throughout the WIO region in recent decades, little is known about the degree to which CBA activities have contributed to achieving the objectives of breaking the cycle of poverty and environmental degradation and promoting community development and biodiversity conservation. In order to improve understanding of common challenges and to generate recommendations for best practice, we assessed the most common CBA activities practiced in the region through literature review and workshop discussion involving practitioners and key stakeholders. Findings indicated that despite favorable environmental conditions for various CBA practices, the sector remains underdeveloped, with few activities delivering the intended benefits for coastal livelihoods or conservation. Constraints included a shortage of seed and feed supplies, low investment, limited technical capacity and skills, insufficient political support, and lack of a clear strategy for aquaculture development. These are compounded by a lack of engagement of local stakeholders, with decision making often dominated by donors, development agencies, and private sector partners. Many of the region’s CBA projects are designed along unrealistically short time frames, driven by donors rather than entrepreneurs, and so are unable to achieve financial sustainability, which limits the opportunity for capacity building and longer-term development. There is little or no monitoring on ecological and socioeconomic impacts. Except for a few isolated cases, links between CBA and marine conservation outcomes have rarely been demonstrated. Realizing the potential of CBA in contributing toward food security in the WIO will necessitate concerted investment and capacity strengthening to overcome these systemic challenges in the sector. Lessons herein offer managers, scientists, and policy advisors guidance on addressing the challenges faced in building strategic development initiatives around aquaculture in developing countries