Demonstration of Cross-Protective Vaccine Immunity against an Emerging Pathogenic Ebolavirus Species

A major challenge in developing vaccines for emerging pathogens is their continued evolution and ability to escape human immunity. Therefore, an important goal of vaccine research is to advance vaccine candidates with sufficient breadth to respond to new outbreaks of previously undetected viruses. Ebolavirus (EBOV) vaccines have demonstrated protection against EBOV infection in nonhuman primates (NHP) and show promise in human clinical trials but immune protection occurs only with vaccines whose antigens are matched to the infectious challenge species. A 2007 hemorrhagic fever outbreak in Uganda demonstrated the existence of a new EBOV species, Bundibugyo (BEBOV), that differed from viruses covered by current vaccine candidates by up to 43% in genome sequence. To address the question of whether cross-protective immunity can be generated against this novel species, cynomolgus macaques were immunized with DNA/rAd5 vaccines expressing ZEBOV and SEBOV glycoprotein (GP) prior to lethal challenge with BEBOV. Vaccinated subjects developed robust, antigen-specific humoral and cellular immune responses against the GP from ZEBOV as well as cellular immunity against BEBOV GP, and immunized macaques were uniformly protected against lethal challenge with BEBOV. This report provides the first demonstration of vaccine-induced protective immunity against challenge with a heterologous EBOV species, and shows that Ebola vaccines capable of eliciting potent cellular immunity may provide the best strategy for eliciting cross-protection against newly emerging heterologous EBOV species

Eculizumab treatment: stochastic occurrence of C3 binding to individual PNH erythrocytes

C5 blockade by eculizumab prevents complement-mediated intravascular hemolysis in paroxysmal nocturnal hemoglobinuria (PNH). However, C3-bound PNH red blood cells (RBCs), arising in almost all treated patients, may undergo extravascular hemolysis reducing clinical benefits. Despite the uniform deficiency of CD55 and of CD59, there are always two distinct populations of PNH RBCs, with (C3+) and without (C3-) C3 binding

A high-resolution linkage map for comparative genome analysis and QTL fine mapping in Asian seabass, Lates calcarifer

10.1186/1471-2164-12-174BMC Genomics12-BGME

One size doesn’t fit all: cross-sectional associations between neighborhood walkability, crime and physical activity depends on age and sex of residents

Abstract Background Low-income African American adults are disproportionately affected by obesity and are also least likely to engage in recommended levels of physical activity (Flegal et al. JAMA 303(3):235-41, 2010; Tucker et al. Am J Prev Med 40(4):454-61, 2011). Moderate-to-vigorous physical activity (MVPA) is an important factor for weight management and control, as well as for reducing disease risk (Andersen et al. Lancet 368(9532):299-304, 2006; Boreham and Riddoch J Sports Sci 19(12):915-29, 2001; Carson et al. PLoS One 8(8):e71417, 2013). While neighborhood greenspace and walkability have been associated with increased MVPA, evidence also suggests that living in areas with high rates of crime limits MVPA. Few studies have examined to what extent the confluence of neighborhood greenspace, walkability and crime might impact MVPA in low-income African American adults nor how associations may vary by age and sex. Methods In 2013 we collected self-reported data on demographics, functional limitations, objective measures of MVPA (accelerometry), neighborhood greenspace (geographic information system), and walkability (street audit) in 791 predominantly African-American adults (mean age 56 years) living in two United States (U.S.) low-income neighborhoods. We also acquired data from the City of Pittsburgh on all crime events within both neighborhoods. Exposure: To examine cross-sectional associations of neighborhood-related variables (i.e., neighborhood greenspace, walkability and crime) with MVPA, we used zero-inflated negative binomial regression models. Additionally, we examined potential interactions by age (over 65 years) and sex on relationships between neighborhood variables and MVPA. Results Overall, residents engaged in very little to no MVPA regardless of where they lived. However, for women, but not men, under the age of 65 years, living in more walkable neighborhoods was associated with more time engaged in MVPA in (β = 0.55, p = 0.007) as compared to their counterparts living in less walkable areas. Women and men age 65 years and over spent very little time participating in MVPA regardless of neighborhood walkability. Neither greenspace nor crime was associated with MVPA in age-sex subgroups. Conclusions Neighborhood walkability may play a stronger role on MVPA than accessible greenspace or crime in low-income urban communities. Walkability may differentially impact residents depending on their age and sex, which suggests tailoring public health policy design and implementation according to neighborhood demographics to improve activity for all.http://deepblue.lib.umich.edu/bitstream/2027.42/135725/1/12889_2016_Article_3959.pd

B Cell Depletion in HIV-1 Subtype A Infected Ugandan Adults: Relationship to CD4 T Cell Count, Viral Load and Humoral Immune Responses

To better understand the nature of B cell dysfunctions in subjects infected with HIV-1 subtype A, a rural cohort of 50 treatment-naïve Ugandan patients chronically infected with HIV-1 subtype A was studied, and the relationship between B cell depletion and HIV disease was assessed. B cell absolute counts were found to be significantly lower in HIV-1+ patients, when compared to community matched negative controls (p<0.0001). HIV-1-infected patients displayed variable functional and binding antibody titers that showed no correlation with viral load or CD4+ T cell count. However, B cell absolute counts were found to correlate inversely with neutralizing antibody (NAb) titers against subtype A (p = 0.05) and subtype CRF02_AG (p = 0.02) viruses. A positive correlation was observed between subtype A gp120 binding antibody titers and NAb breadth (p = 0.02) and mean titer against the 10 viruses (p = 0.0002). In addition, HIV-1 subtype A sera showed preferential neutralization of the 5 subtype A or CRF02_AG pseudoviruses, as compared with 5 pseudoviruses from subtypes B, C or D (p<0.001). These data demonstrate that in patients with chronic HIV-1 subtype A infection, significant B cell depletion can be observed, the degree of which does not appear to be associated with a decrease in functional antibodies. These findings also highlight the potential importance of subtype in the specificity of cross-clade neutralization in HIV-1 infection

LRRK2 Biology from structure to dysfunction: research progresses, but the themes remain the same

Since the discovery of leucine-rich repeat kinase 2 (LRRK2) as a protein that is likely central to the aetiology of Parkinson's disease, a considerable amount of work has gone into uncovering its basic cellular function. This effort has led to the implication of LRRK2 in a bewildering range of cell biological processes and pathways, and probable roles in a number of seemingly unrelated medical conditions. In this review we summarise current knowledge of the basic biochemistry and cellular function of LRRK2. Topics covered include the identification of phosphorylation substrates of LRRK2 kinase activity, in particular Rab proteins, and advances in understanding the activation of LRRK2 kinase activity via dimerisation and association with membranes, especially via interaction with Rab29. We also discuss biochemical studies that shed light on the complex LRRK2 GTPase activity, evidence of roles for LRRK2 in a range of cell signalling pathways that are likely cell type specific, and studies linking LRRK2 to the cell biology of organelles. The latter includes the involvement of LRRK2 in autophagy, endocytosis, and processes at the trans-Golgi network, the endoplasmic reticulum and also key microtubule-based cellular structures. We further propose a mechanism linking LRRK2 dimerisation, GTPase function and membrane recruitment with LRRK2 kinase activation by Rab29. Together these data paint a picture of a research field that in many ways is moving forward with great momentum, but in other ways has not changed fundamentally. Many key advances have been made, but very often they seem to lead back to the same places

Consensus guidelines for the use and interpretation of angiogenesis assays

The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and development, tissue and organ regeneration, as well as numerous pathological conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantified by a large number of bioassays. These independent assessments hold advantages but also have limitations. This article describes in vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis and highlights critical aspects that are relevant for their execution and proper interpretation. As such, this collaborative work is the first edition of consensus guidelines on angiogenesis bioassays to serve for current and future reference