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Broadly neutralizing antibodies against highly variable viral pathogens are much sought after to treat or protect against global circulating viruses. Here we probed the neutralizing antibody repertoires of four human immunodeficiency virus (HIV)-infected donors with remarkably broad and potent neutralizing responses and rescued 17 new monoclonal antibodies that neutralize broadly across clades. Many of the new monoclonal antibodies are almost tenfold more potent than the recently described PG9, PG16 and VRC01 broadly neutralizing monoclonal antibodies and 100-fold more potent than the original prototype HIV broadly neutralizing monoclonal antibodies 1 , 2 , 3 . The monoclonal antibodies largely recapitulate the neutralization breadth found in the corresponding donor serum and many recognize novel epitopes on envelope (Env) glycoprotein gp120, illuminating new targets for vaccine design. Analysis of neutralization by the full complement of anti-HIV broadly neutralizing monoclonal antibodies now available reveals that certain combinations of antibodies should offer markedly more favourable coverage of the enormous diversity of global circulating viruses than others and these combinations might be sought in active or passive immunization regimes. Overall, the isolation of multiple HIV broadly neutralizing monoclonal antibodies from several donors that, in aggregate, provide broad coverage at low concentrations is a highly positive indicator for the eventual design of an effective antibody-based HIV vaccine.

Broadly neutralizing antibodies (bNAbs), which develop over time in some HIV-1-infected individuals, define critical epitopes for HIV vaccine design. Using a systematic approach, we have examined neutralization breadth in the sera of about 1800 HIV-1-infected individuals, primarily infected with non-clade B viruses, and have selected donors for monoclonal antibody (mAb) generation. We then used a high-throughput neutralization screen of antibody-containing culture supernatants from about 30,000 activated memory B cells from a clade A-infected African donor to isolate two potent mAbs that target a broadly neutralizing epitope. This epitope is preferentially expressed on trimeric Envelope protein and spans conserved regions of variable loops of the gp120 subunit. The results provide a framework for the design of new vaccine candidates for the elicitation of bNAb responses.

Influenza remains a serious public health threat throughout the world. Vaccines and antivirals are available that can provide protection from infection. However, new viral strains emerge continuously because of the plasticity of the influenza genome, which necessitates annual reformulation of vaccine antigens, and resistance to antivirals can appear rapidly and become entrenched in circulating virus populations. In addition, the spread of new pandemic strains is difficult to contain because of the time required to engineer and manufacture effective vaccines. Monoclonal antibodies that target highly conserved viral epitopes might offer an alternative protection paradigm. Herein we describe the isolation of a panel of monoclonal antibodies derived from the IgG⁺ memory B cells of healthy, human subjects that recognize a previously unknown conformational epitope within the ectodomain of the influenza matrix 2 protein, M2e. This antibody binding region is highly conserved in influenza A viruses, being present in nearly all strains detected to date, including highly pathogenic viruses that infect primarily birds and swine, and the current 2009 swine-origin H1N1 pandemic strain (S-OIV). Furthermore, these human anti-M2e monoclonal antibodies protect mice from lethal challenges with either H5N1 or H1N1 influenza viruses. These results suggest that viral M2e can elicit broadly cross-reactive and protective antibodies in humans. Accordingly, recombinant forms of these human antibodies may provide useful therapeutic agents to protect against infection from a broad spectrum of influenza A strains.

This dissertation examines three novels by contemporary French author Sylvie Germain. Germain was born in 1954, and completed a doctorate from the Université de Paris-Nanterre in 1981, after which she began to write fiction. Her first novel, Le Livre des Nuits, was published in 1985, and since then she has published several more novels as well as numerous essays. The story of Jacob's fight with the angel in Genesis 32 is a key intertext of Sylvie Germain's œuvre and a preliminary link between the three themes this dissertation analyzes in her novels. When he defeats the angel, Jacob names the spot \"Penuel,\" which means \"face of God\" (Gen. 32:30). He thus inscribes the story of his encounter with God upon the place, and acknowledges the singularity of seeing God face-to-face. In the three works studied here (Nuit-d'Ambre , 1987; La Pleurante des rues de Prague, 1992; and Immensités, 1993), places are shown to be texts; that is, places hold stories that have been inscribed on them in the past and which Germain brings to the surface. Face-to-face encounters in her novels are also turned into textual events on the margins of perception, but here it is the command \"Thou shalt not kill\" that is silently expressed, revealing the influence of philosopher Emmanuel Levinas. Germain's writing of place and face opens the way for an understanding of the word \"God\" that also exists on the margins of comprehension. Rather than being a usual word with a known referent, the word \"God\" instead names a call and response structure. Germain places her characters in situations where they have the opportunity to act according to an ethics of attentiveness: to history, to the marginalized, to the silent and silenced, to the face of the other, and to the call and response of the word \"God.\" It is in hearing the part of silence in speech, and in seeing the part of the unwritable in text, that characters find a partial reconciliation with the other person and with the world.

Neutrophils and platelets interact both physically and metabolically during inflammation and thrombosis, but the mechanisms responsible for their adhesion remain incompletely understood. Neutrophil-platelet adhesion was measured after specific stimulation of neutrophils, platelets, or both and quantified by flow cytometry. Specific stimulation of either the neutrophil or the platelet led to a marked increase in the percentage of neutrophils that bound platelets, although platelet stimulation led to a large increase and neutrophil stimulation to only a small increase in the number of platelets per neutrophil. Stimulation of both cells further increased the number of neutrophil-platelet adhesive events and led to large numbers of platelets binding to each neutrophil. Confirming previous observations, blocking antibodies to platelet P-selectin (CD62P) partially inhibited adhesion. However, blockade of the neutrophil beta2 integrin CD11b/CD18 also inhibited the percentage of neutrophils that bound platelets. Combining P-selectin and CD11b/18 blockade further inhibited the stimulated increase in the percentage of neutrophils binding platelets and the increased number of platelets per neutrophil. Both cell adhesion molecules were active even when only a single cell type was primarily activated, supporting physiologically important transcellular activation. These data suggest that: (1) neutrophil-platelet adhesion can be initiated by specific activation of either the neutrophil or the platelet and that specific activation of either cell type leads to distinct patterns of adhesion, and (2) neutrophil-platelet adhesion uses both platelet P-selectin and the neutrophil beta2 integrin CD11b/CD18 when the cells are primarily or secondarily activated.

Speciation events often occur in rapid bursts of diversification, but the ecological and genetic factors that promote these radiations are still much debated. Using whole transcriptomes from all 13 species in the ecologically and reproductively diverse wild tomato clade (Solanum sect. Lycopersicon), we infer the species phylogeny and patterns of genetic diversity in this group. Despite widespread phylogenetic discordance due to the sorting of ancestral variation, we date the origin of this radiation to approximately 2.5 million years ago and find evidence for at least three sources of adaptive genetic variation that fuel diversification. First, we detect introgression both historically between early-branching lineages and recently between individual populations, at specific loci whose functions indicate likely adaptive benefits. Second, we find evidence of lineage-specific de novo evolution for many genes, including loci involved in the production of red fruit color. Finally, using a \"PhyloGWAS\" approach, we detect environment-specific sorting of ancestral variation among populations that come from different species but share common environmental conditions. Estimated across the whole clade, small but substantial and approximately equal fractions of the euchromatic portion of the genome are inferred to contribute to each of these three sources of adaptive genetic variation. These results indicate that multiple genetic sources can promote rapid diversification and speciation in response to new ecological opportunity, in agreement with our emerging phylogenomic understanding of the complexity of both ancient and recent species radiations.

Elevated rates of evolution in reproductive proteins are commonly observed in animal species, and are thought to be driven by the action of sexual selection and sexual conflict acting specifically on reproductive traits. Whether similar patterns are broadly observed in other biological groups is equivocal. Here, we examine patterns of protein divergence among wild tomato species ( Solanum section Lycopersicon ), to understand forces shaping the evolution of reproductive genes in this diverse, rapidly evolving plant clade. By comparing rates of molecular evolution among loci expressed in reproductive and non-reproductive tissues, our aims were to test if: (a) reproductive-specific loci evolve more rapidly, on average, than non-reproductive loci; (b) ‘male’-specific loci evolve at different rates than ‘female’-specific loci; (c) genes expressed exclusively in gametophytic (haploid) tissue evolve differently from genes expressed in sporophytic (diploid) tissue or in both tissue types; and (d) mating system variation (a potential proxy for the expected strength of sexual selection and/or sexual conflict) affects patterns of protein evolution. We observed elevated evolutionary rates in reproductive proteins. However, this pattern was most evident for female- rather than male-specific loci, both broadly and for individual loci inferred to be positively selected. These elevated rates might be facilitated by greater tissue-specificity of reproductive proteins, as faster rates were also associated with more narrow expression domains. In contrast, we found little evidence that evolutionary rates are consistently different in loci experiencing haploid selection (gametophytic-exclusive loci), or in lineages with quantitatively different mating systems. Overall while reproductive protein evolution is generally elevated in this diverse plant group, some specific patterns of evolution are more complex than those reported in other (largely animal) systems, and include a more prominent role for female-specific loci among adaptively evolving genes.

Abstract Despite the increasing abundance of whole transcriptome data, few methods are available to analyze global gene expression across phylogenies. Here, we present a new software package (Computational Analysis of Gene Expression Evolution [CAGEE]) for inferring patterns of increases and decreases in gene expression across a phylogenetic tree, as well as the rate at which these changes occur. In contrast to previous methods that treat each gene independently, CAGEE can calculate genome-wide rates of gene expression, along with ancestral states for each gene. The statistical approach developed here makes it possible to infer lineage-specific shifts in rates of evolution across the genome, in addition to possible differences in rates among multiple tissues sampled from the same species. We demonstrate the accuracy and robustness of our method on simulated data and apply it to a data set of ovule gene expression collected from multiple self-compatible and self-incompatible species in the genus Solanum to test hypotheses about the evolutionary forces acting during mating system shifts. These comparisons allow us to highlight the power of CAGEE, demonstrating its utility for use in any empirical system and for the analysis of most morphological traits. Our software is available at https://github.com/hahnlab/CAGEE/.

• Genetic correlations among different components of phenotypes, especially those resulting from pleiotropy, can constrain or facilitate trait evolution. These factors could especially influence the evolution of traits that are functionally integrated, such as those comprising the flower. Indeed, pleiotropy is proposed as a main driver of repeated convergent trait transitions, including the evolution of phenotypically similar pollinator syndromes. • We assessed the role of pleiotropy in the differentiation of floral and other reproductive traits between two species – Jaltomata sinuosa and J. umbellata (Solanaceae) – that have divergent suites of floral traits consistent with bee and hummingbird pollination, respectively. To do so, we generated a hybrid population and examined the genetic architecture (trait segregation and quantitative trait locus (QTL) distribution) underlying 25 floral and fertility traits. • We found that most floral traits had a relatively simple genetic basis (few, predominantly additive, QTLs of moderate to large effect), as well as little evidence of antagonistic pleiotropy (few trait correlations and QTL colocalization, particularly between traits of different classes). However, we did detect a potential case of adaptive pleiotropy among floral size and nectar traits. • These mechanisms may have facilitated the rapid floral trait evolution observed within Jaltomata, and may be a common component of rapid phenotypic change more broadly.

Invasive species represent one of the foremost risks to global biodiversity. Here, we use population genomics to evaluate the history and consequences of an invasion of wild tomato— Solanum pimpinellifolium —onto the Galápagos Islands from continental South America. Using >300 archipelago and mainland collections, we infer this invasion was recent and largely the result of a single event from central Ecuador. Patterns of ancestry within the genomes of invasive plants also reveal post-colonization hybridization and introgression between S. pimpinellifolium and the closely related Galápagos endemic Solanum cheesmaniae . Of admixed invasive individuals, those that carry endemic alleles at one of two different carotenoid biosynthesis loci also have orange fruits—characteristic of the endemic species—instead of typical red S. pimpinellifolium fruits. We infer that introgression of two independent fruit color loci explains this observed trait convergence, suggesting that selection has favored repeated transitions of red to orange fruits on the Galápagos.