Programming the magnitude and persistence of antibody responses with innate immunity

Many successful vaccines induce persistent antibody responses that can last a lifetime. The mechanisms by which they do so remain unclear, but emerging evidence indicates that they activate dendritic cells via Toll-like receptors (TLRs). For example, the yellow fever vaccine YF-17D, one of the most successful empiric vaccines ever developed, activates dendritic cells via multiple TLRs to stimulate proinflammatory cytokines. Triggering specific combinations of TLRs in dendritic cells can induce synergistic production of cytokines, which results in enhanced T-cell responses, but its impact on antibody responses remain unknown. Learning the critical parameters of innate immunity that program such antibody responses remains a major challenge in vaccinology. Here we demonstrate that immunization of mice with synthetic nanoparticles containing antigens plus ligands that signal through TLR4 and TLR7 induces synergistic increases in antigen-specific, neutralizing antibodies compared to immunization with nanoparticles containing antigens plus a single TLR ligand. Consistent with this there was enhanced persistence of germinal centres and of plasma-cell responses, which persisted in the lymph nodes for >1.5 years. Surprisingly, there was no enhancement of the early short-lived plasma-cell response relative to that observed with single TLR ligands. Molecular profiling of activated B cells, isolated 7 days after immunization, indicated that there was early programming towards B-cell memory. Antibody responses were dependent on direct triggering of both TLRs on B cells and dendritic cells, as well as on T-cell help. Immunization protected completely against lethal avian and swine influenza virus strains in mice, and induced robust immunity against pandemic H1N1 influenza in rhesus macaques.     

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140?mm?Hg systolic blood pressure or ≥90?mm?Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.     

Phase stability in high entropy alloys: Formation of solid-solution phase or amorphous phase

The alloy design for equiatomic multi-component alloys was rationalized by statistically analyzing the atomic size difference, mixing enthalpy, mixing entropy, electronegativity, valence electron concentration among constituent elements in solid solutions forming high entropy alloys and amorphous alloys. Solid solution phases form and only form when the requirements of the atomic size difference, mixing enthalpy and mixing entropy are all met. The most significant difference between the solid solution forming high entropy alloys and bulk metallic glasses lies in the atomic size difference. These rules provide valuable guidance for the future development of high entropy alloys and bulk metallic glasses.     

Effects of various media on tissular and cellular structures of the superior cervical ganglion of the rat.

The superior cervical ganglia of the rat have been incubated in vitro for 1 h in basal medium Eagle (BME) with Hanks' salts, BME with Earle's salts, Kreb's solution and NCTC 109 medium. Comparison of the cell areas, established by a semi-automatic quantitative method, shows that the three former induce a 30--35% neuronal retraction, whereas NCTC 109 has no effect. Thus this latter medium seems the best one for studies using incubation of these cells.     

Differentiating abilities of avian somatopleural mesoderm.

Quail-to-chick grafting experiments were performed on 2-day embryos in order to test the differentiating abilities of the somatopleure. After orthotopic and heterotopic transplatations of different parts of quail somatopleural mesoderm into chick embryos it is demonstrated that avian somatopleural cells differentiate into skeletal elements, smooth muscles, tendons and connective tissues. However, skeletal muscle fibres do not originate from somatopleural cells.     

Synapse-like profiles in regenerating sensory nerve fibres of Herbst corpuscles.

During regeneration sequences of Herbst corpuscles, the synapse-like structures are described between pairs of non-myelinated sensory profiles. The probable significance of this unusual for sensory corpuscles finding is discussed.     

Structure specificity of some immunoadjuvant synthetic glycopeptides.

The immunoadjuvant activity of muramyl dipeptide seems to be critically dependent on the type of substitution of the gamma-carboxyl group of the D-isoglutamine residue. Moreover the nonapeptide L-Ala-D-isoGlu-L-lys-D-Ala-(Gly)5-OME also shows a definite effect.     

Plasma steroid and protein hormone concentrations in patients with benign prostatic hypertrophy and in normal men.

Serum levels of testosterone, FSH, LH and prolactin were measured by RIA in patients with BPH (benign prostatic hypertrophy) and in control men. The testosterone concentrations in the BPH group were significantly lower than that of the control group. Serum concentrations of FSH, LH, prolactin and estradiol, did not differ significantly in the 2 groups.     

Skeletal muscle capillary densities during reactive hyperemia

Reactive hyperemia was induced in hindlimbs of rats by occlusion of the femoral artery. Using fluorescein dye as a peripheral vascular marker, we observed that there was an increase in the number of flowing capillaries supplying the muscle fibres following release of the occlusion. The results indicate that the number of flowing capillaries is not dependent on the duration of occlusion (2-10 min).