Potent Dengue virus neutralization by a therapeutic antibody with low monovalent affinity requires bivalent engagement

We recently described our most potently neutralizing monoclonal antibody, E106, which protected against lethal Dengue virus type 1 (DENV-1) infection in mice. To further understand its functional properties, we determined the crystal structure of E106 Fab in complex with domain III (DIII) of DENV-1 envelope (E) protein to 2.45 Å resolution. Analysis of the complex revealed a small antibody-antigen interface with the epitope on DIII composed of nine residues along the lateral ridge and A-strand regions. Despite strong virus neutralizing activity of E106 IgG at picomolar concentrations, E106 Fab exhibited a ∼20,000-fold decrease in virus neutralization and bound isolated DIII, E, or viral particles with only a micromolar monovalent affinity. In comparison, E106 IgG bound DENV-1 virions with nanomolar avidity. The E106 epitope appears readily accessible on virions, as neutralization was largely temperature-independent. Collectively, our data suggest that E106 neutralizes DENV-1 infection through bivalent engagement of adjacent DIII subunits on a single virion. The isolation of anti-flavivirus antibodies that require bivalent binding to inhibit infection efficiently may be a rare event due to the unique icosahedral arrangement of envelope proteins on the virion surface

Solar vs. Fission Surface Power for Mars

A multi-discipline team of experts from the National Aeronautics and Space Administration (NASA) developed Mars surface power system point design solutions for two conceptual missions. The primary goal of this study was to compare the relative merits of solar- versus fission-powered versions of each surface mission. First, the team compared three different solar power options against a fission power system concept for a sub-scale, uncrewed demonstration mission. The 4.5 meter (m) diameter pathfinder lander's primary mission would be to demonstrate Mars entry, descent, and landing techniques. Once on the Martian surface, the lander's In Situ Resource Utilization (ISRU) payload would demonstrate liquid oxygen propellant production using atmospheric resources. For the purpose of this exercise, location was assumed to be at the Martian equator. The three solar concepts considered included a system that only operated during daylight hours (at roughly half the daily propellant production rate of a round-the-clock fission design), a battery-augmented system that operated through the night (matching the fission concept's propellant production rate), and a system that operated only during daylight, but at a higher rate (again, matching the fission concept's propellant production rate). Including 30% mass growth allowance, total payload masses for the three solar concepts ranged from 1,116 to 2,396 kg, versus the 2,686 kg fission power scheme. However, solar power masses are expected to approach or exceed the fission payload mass at landing sites further from the equator, making landing site selection a key driver in the final power system decision. The team also noted that detailed reliability analysis should be performed on daytime-only solar power schemes to assess potential issues with frequent ISRU system on/off cycling. Next, the team developed a solar-powered point design solution for a conceptual four-crew, 500-day surface mission consisting of up to four landers per crewed expedition mission. Unlike the demonstration mission, a lengthy power outage due to the global dust storms that are known to occur on Mars would pose a safety hazard to a crewed mission. A similar fission versus solar power trade study performed by NASA in 2007 concluded that fission power was more reliable-with a much lower mass penalty-than solar power for this application. However, recent advances in solar cell and energy storage technologies and changes in operational assumptions prompted NASA to revisit the analysis. For the purpose of this exercise a particular landing site at Jezero Crater, located at 18o north latitude, was assumed. A fission power system consisting of four each 10 kW Kilopower fission reactors was compared to a distributed network of Orion-derived Ultraflex solar arrays and Lithium ion batteries mounted on every lander. The team found that a solar power system mass of about 9,800 kg would provide the 22 kilowatts (kW) keep-alive power needed to survive a dust storm lasting up to 120-days at average optical depth of 5, and 35 kW peak power for normal operations under clear skies. Although this is less than half the mass estimated during the 2007 work (which assumed latitudes up to 30o) it is still more than the 7,000 kg mass of the fission system which provides full power regardless of dust storm conditions

Megakaryocytes possess a functional intrinsic apoptosis pathway that must be restrained to survive and produce platelets

Deletion of Bak and Bax, the effectors of mitochondrial apoptosis, does not affect platelet production, however, loss of prosurvival Bcl-xL results in megakaryocyte apoptosis and failure of platelet shedding

Evidence of an Antimicrobial-Immunomodulatory Role of Atlantic Salmon Cathelicidins during Infection with Yersinia ruckeri

Cathelicidins are a family of antimicrobial peptides that act as effector molecules of the innate immune system with broad-spectrum antimicrobial properties. These evolutionary conserved cationic host-defence peptides are integral components of the immune response of fish, which are generally believed to rely heavily on innate immune defences to invading pathogens. In this study we showed that Atlantic salmon cathelicidin 1 and 2 (asCATH1 and asCATH2) stimulated peripheral blood leukocytes increasing the transcription of the chemokine interleukin-8. Further, functional differences were identified between the two cathelicidins. In the presence of serum, asCATH1 displayed greatly diminished host haemolytic activity, while the constitutively expressed asCATH2 had no haemolytic activity with or without serum. These findings support our hypothesis that fish cathelicidins exert their primary antimicrobial action at the site of pathogen invasion such as epithelial surfaces. Further, we hypothesise that like their mammalian counterparts in the presence of serum they act as mediators of the innate and adaptive immune response via the release of cytokines thus indirectly protecting against a variety of pathogens. We highlight the importance of this immunomodulatory role from the involvement of asCATHs during an infection with the fish pathogen Yersinia ruckeri. While we were able to demonstrate in vitro that asCATH1 and 2, possessed direct microbicidal activity against the fish pathogen, Vibrio anguillarum, and a common gram negative bacterium, Escherichia coli, little or no bactericidal activity was found against Y. ruckeri. The contribution of either asCATH in the immune response or as a potential virulence factor during yersiniosis is highlighted from the increased expression of asCATH1 and 2 mRNA during an in vivo challenge with Y. ruckeri . We propose that Atlantic salmon cathelicidins participate in the interplay between the innate and adaptive immune systems via the release of cytokines enabling a more effective response to invading pathogens

Influenza vaccination for immunocompromised patients: systematic review and meta-analysis from a public health policy perspective.

Immunocompromised patients are vulnerable to severe or complicated influenza infection. Vaccination is widely recommended for this group. This systematic review and meta-analysis assesses influenza vaccination for immunocompromised patients in terms of preventing influenza-like illness and laboratory confirmed influenza, serological response and adverse events

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

The Familiar Essay in American Literature

418 p.Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 1968.U of I OnlyRestricted to the U of I community idenfinitely during batch ingest of legacy ETD

The genealogy of Peiter Heyl and his descendants, 1100-1936 : with the intermarried families of Arnold, Bess, Byrd, Cansler, Carlock, Carpenter, Costner (Kestner) Davis, Freeman, Friday, Gantt (Gaunt, Ghent) Green, Hahn, Henkel, Hoffman, Hovis, Huffstetler, Jones, Klein, Lineberger (Leinberger) Mendenhall, McIntosh, Nesbitt, Payne, Patton, Peel, Peeler, Porter, Ramsour, Reinhardt, Rhyne, Reynolds, Robinson, Rudisill, Shuford, Summey, Smith, Thompson, Wells, Warlick, Weidner, and Wilfong /

Mode of access: Internet