Antigen-Independent Selection of T15 Idiotype During B-Cell Ontogeny In Mice

Precursors of B cells capable of responding to a T-independent form of phosphorylcholine (PC) in splenic focus assays were detected in the spleens of neonatal mice as early as 4 days after birth. The earliest anti-PC B cells were T15-. T15+ foci-forming B cells were first detected 6 days after birth and expanded rapidly to constitute greater than 80% of the total PC-specific foci by day 10. Injection of heat-killed S. pneumoniae (R36A) into neonatal mice resulted in priming of the antibody response to PC, with an idiotype profile reflecting that of precursors of foci-forming B cells at the time of antigen administration. Priming of 2-dayold mice with 2 X106 and 2 X107 R36A induced a five- and ten-fold increase in the antibody response to phosphorylcholine 6 to 8 weeks later. However, only 10 to 15% of the serum antibodies expressed the normally dominant T15 idiotype. Doses below 2 x105 R36A showed no detectable priming activity. PC-specific hybridomas derived from mice injected with 2 X107 R36A 2 days after birth lacked the idiotypic and molecular characteristics typical of T15+ antibodies. Antibodies to phosphorylcholine, raised by immunization of 6-week-old mice are normally protective against pneumococcal infection. However, serum antibodies from mice treated with R36A 2 days after birth and responding to phosphorylcholine following challenge with R36A at 6 weeks of age failed to protect against deliberate infection with virulent S. pneumoniae. These observations imply that the antigen phosphorylcholine does not play a role in the selective expansion and dominant expression of the T15 idiotype

Relative Fitness of Fluoroquinolone-resistant Streptococcus pneumoniae

Fluoroquinolone resistance in Streptococcus pneumoniae is primarily mediated by point mutations in the quinolone resistance–determining regions of gyrA and parC. Antimicrobial resistance mutations in housekeeping genes often decrease fitness of microorganisms. To investigate the fitness of quinolone-resistant S. pneumoniae (QRSP), the relative growth efficiencies of 2 isogenic QRSP double mutants were compared with that of their fluoroquinolone-susceptible parent, EF3030, by using murine nasopharyngeal colonization and pneumonia models. Strains containing the GyrA: Ser81Phe, ParC: Ser79Phe double mutations, which are frequently seen in clinical QRSP, competed poorly with EF3030 in competitive colonization or competitive lung infections. However, they efficiently produced lung infection even in the absence of EF3030. The strain containing the GyrA: Ser81Phe, ParC: Ser79Tyr double mutations, which is seen more frequently in laboratory-derived QRSP than in clinical QRSP, demonstrated reduced nasal colonization in competitive or noncompetitive lung infections. However, the strain was equally able to cause competitive or noncompetitive lung infections as well as EF3030

A Kerr-microresonator optical clockwork

Kerr microresonators generate interesting and useful fundamental states of electromagnetic radiation through nonlinear interactions of continuous-wave (CW) laser light. Using photonic-integration techniques, functional devices with low noise, small size, low-power consumption, scalable fabrication, and heterogeneous combinations of photonics and electronics can be realized. Kerr solitons, which stably circulate in a Kerr microresonator, have emerged as a source of coherent, ultrafast pulse trains and ultra-broadband optical-frequency combs. Using the f-2f technique, Kerr combs support carrier-envelope-offset phase stabilization for optical synthesis and metrology. In this paper, we introduce a Kerr-microresonator optical clockwork based on optical-frequency division (OFD), which is a powerful technique to transfer the fractional-frequency stability of an optical clock to a lower frequency electronic clock signal. The clockwork presented here is based on a silicon-nitride (Si$_3$N$_4$) microresonator that supports an optical-frequency comb composed of soliton pulses at 1 THz repetition rate. By electro-optic phase modulation of the entire Si$_3$N$_4$ comb, we arbitrarily generate additional CW modes between the Si$_3$N$_4$ comb modes; operationally, this reduces the pulse train repetition frequency and can be used to implement OFD to the microwave domain. Our experiments characterize the residual frequency noise of this Kerr-microresonator clockwork to one part in $10^{17}$, which opens the possibility of using Kerr combs with high performance optical clocks. In addition, the photonic integration and 1 THz resolution of the Si$_3$N$_4$ frequency comb makes it appealing for broadband, low-resolution liquid-phase absorption spectroscopy, which we demonstrate with near infrared measurements of water, lipids, and organic solvents

Maternal Immunization with Pneumococcal Surface Protein A Protects against Pneumococcal Infections among Derived Offspring

Pathogen-specific antibody plays an important role in protection against pneumococcal carriage and infections. However, neonates and infants exhibit impaired innate and adaptive immune responses, which result in their high susceptibility to pneumococci. To protect neonates and infants against pneumococcal infection it is important to elicit specific protective immune responses at very young ages. In this study, we investigated the protective immunity against pneumococcal carriage, pneumonia, and sepsis induced by maternal immunization with pneumococcal surface protein A (PspA). Mother mice were intranasally immunized with recombinant PspA (rPspA) and cholera toxin B subunit (CTB) prior to being mated. Anti-PspA specific IgG, predominantly IgG1, was present at a high level in the serum and milk of immunized mothers and in the sera of their pups. The pneumococcal densities in washed nasal tissues and in lung homogenate were significantly reduced in pups delivered from and/or breast-fed by PspA-immunized mothers. Survival after fatal systemic infections with various types of pneumococci was significantly extended in the pups, which had received anti-PspA antibody via the placenta or through their milk. The current findings strongly suggest that maternal immunization with PspA is an attractive strategy against pneumococcal infections during early childhood. (191 words

Disruption of cultural burning promotes shrub encroachment and unprecedented wildfires

Recent catastrophic fires in Australia and North America have raised broad-scale questions about how the cessation of Indigenous burning practices has impacted fuel accumulation and structure. For sustainable coexistence with fire, a better understanding of the ancient nexus between humans and flammable landscapes is needed. We used novel palaeoecological modeling and charcoal compilations to reassess evidence for changes in land cover and fire activity, focusing on southeast Australia before and after British colonization. Here, we provide what we believe is the first quantitative evidence that the region’s forests and woodlands contained fewer shrubs and more grass before colonization. Changes in vegetation, fuel structures, and connectivity followed different trajectories in different vegetation types. The pattern is best explained by the disruption of Indigenous vegetation management caused by European settlement. Combined with climate-change impacts on fire weather and drought, the widespread absence of Indigenous fire management practices likely preconditioned fire-prone regions for wildfires of unprecedented extent

Nanogel-Based PspA Intranasal Vaccine Prevents Invasive Disease and Nasal Colonization by Streptococcus pneumoniae

ABSTRACT To establish a safer and more effective vaccine against pneumococcal respiratory infections, current knowledge regarding the antigens common among pneumococcal strains and improvements to the system for delivering these antigens across the mucosal barrier must be integrated. We developed a pneumococcal vaccine that combines the advantages of pneumococcal surface protein A (PspA) with a nontoxic intranasal vaccine delivery system based on a nanometer-sized hydrogel (nanogel) consisting of a cationic cholesteryl group-bearing pullulan (cCHP). The efficacy of the nanogel-based PspA nasal vaccine (cCHP-PspA) was tested in murine pneumococcal airway infection models. Intranasal vaccination with cCHP-PspA provided protective immunity against lethal challenge with Streptococcus pneumoniae Xen10, reduced colonization and invasion by bacteria in the upper and lower respiratory tracts, and induced systemic and nasal mucosal Th17 responses, high levels of PspA-specific serum immunoglobulin G (IgG), and nasal and bronchial IgA antibody responses. Moreover, there was no sign of PspA delivery by nanogel to either the olfactory bulbs or the central nervous system after intranasal administration. These results demonstrate the effectiveness and safety of the nanogel-based PspA nasal vaccine system as a universal mucosal vaccine against pneumococcal respiratory infection

Structure and dynamics of the pan-genome of Streptococcus pneumoniae and closely related species

Background Streptococcus pneumoniae is one of the most important causes of microbial diseases in humans. The genomes of 44 diverse strains of S. pneumoniae were analyzed and compared with strains of non-pathogenic streptococci of the Mitis group. Results Despite evidence of extensive recombination, the S. pneumoniae phylogenetic tree revealed six major lineages. With the exception of serotype 1, the tree correlated poorly with capsular serotype, geographical site of isolation and disease outcome. The distribution of dispensable genes, genes present in not all, but more than one strain, was consistent with phylogeny, although horizontal gene transfer events attenuated this correlation in the case of ancient lineages. Homologous recombination, involving short stretches of DNA, was the dominant 13 evolutionary process of the core genome of S. pneumoniae. Genetic exchange occurred both within and across the borders of the species, and S. mitis was the main reservoir of genetic diversity of S. pneumoniae. The pan-genome size of S. pneumoniae increased logarithmically with the number of strains and linearly with the number of polymorphic sites of the sampled genomes, suggesting that acquired genes accumulate proportionately to the age of clones. Most genes associated with pathogenicity were shared by all S. pneumoniae strains, but were also present in S. mitis, S. oralis and S. infantis, indicating that these genes are not sufficient to determine virulence. Conclusion Genetic exchange with related species sharing the same ecological niche is the main mechanism of evolution of S. pneumoniae. The open pan genome guarantees the species a quick and economical response to diverse environments