Adenovirus Vector Vaccination Impacts NK Cell Rheostat Function following Lymphocytic Choriomeningitis Virus Infection

ABSTRACT Natural killer (NK) cells respond rapidly as a first line of defense against infectious pathogens. In addition, NK cells may provide a “rheostat” function and have been shown to reduce the magnitude of antigen-specific T cell responses following infection to avoid immunopathology. However, it remains unknown whether NK cells similarly modulate vaccine-elicited T cell responses following virus challenge. We used the lymphocytic choriomeningitis virus (LCMV) clone 13 infection model to address whether NK cells regulate T cell responses in adenovirus vector-vaccinated mice following challenge. As expected, NK cell depletion in unvaccinated mice resulted in increased virus-specific CD4+ and CD8+ T cell responses and immunopathology following LCMV challenge. In contrast, NK cell depletion had minimal to no impact on antigen-specific T cell responses in mice that were vaccinated with an adenovirus serotype 5 (Ad5)-GP vector prior to LCMV challenge. Moreover, NK cell depletion in vaccinated mice prior to challenge did not result in immunopathology and did not compromise protective efficacy. These data suggest that adenovirus vaccine-elicited T cells may be less sensitive to NK cell rheostat regulation than T cells primed by LCMV infection. IMPORTANCE: Recent data have shown that NK cell depletion leads to enhanced virus-elicited T cell responses that can result in severe immunopathology following LCMV infection in mice. In this study, we observed that NK cells exerted minimal to no impact on vaccine-elicited T cells following LCMV challenge, suggesting that adenovirus vaccine-elicited T cells may be less subject to NK cell regulation. These data contribute to our understanding of NK cell regulatory functions and T cell-based vaccines

Rates of Mutation and Host Transmission for an Escherichia coli Clone over 3 Years

Although over 50 complete Escherichia coli/Shigella genome sequences are available, it is only for closely related strains, for example the O55:H7 and O157:H7 clones of E. coli, that we can assign differences to individual evolutionary events along specific lineages. Here we sequence the genomes of 14 isolates of a uropathogenic E. coli clone that persisted for 3 years within a household, including a dog, causing a urinary tract infection (UTI) in the dog after 2 years. The 20 mutations observed fit a single tree that allows us to estimate the mutation rate to be about 1.1 per genome per year, with minimal evidence for adaptive change, including in relation to the UTI episode. The host data also imply at least 6 host transfer events over the 3 years, with 2 lineages present over much of that period. To our knowledge, these are the first direct measurements for a clone in a well-defined host community that includes rates of mutation and host transmission. There is a concentration of non-synonymous mutations associated with 2 transfers to the dog, suggesting some selection pressure from the change of host. However, there are no changes to which we can attribute the UTI event in the dog, which suggests that this occurrence after 2 years of the clone being in the household may have been due to chance, or some unknown change in the host or environment. The ability of a UTI strain to persist for 2 years and also to transfer readily within a household has implications for epidemiology, diagnosis, and clinical intervention

Activator Control of Nucleosome Occupancy in Activation and Repression of Transcription

The relationship between chromatin structure and gene expression is a subject of intense study. The universal transcriptional activator Gal4 removes promoter nucleosomes as it triggers transcription, but how it does so has remained obscure. The reverse process, repression of transcription, has often been correlated with the presence of nucleosomes. But it is not known whether nucleosomes are required for that effect. A new quantitative assay describes, for any given location, the fraction of DNA molecules in the population that bears a nucleosome at any given instant. This allows us to follow the time courses of nucleosome removal and reformation, in wild-type and mutant cells, upon activation (by galactose) and repression (by glucose) of the GAL genes of yeast. We show that upon being freed of its inhibitor Gal80 by the action of galactose, Gal4 quickly recruits SWI/SNF to the genes, and that nucleosome “remodeler” rapidly removes promoter nucleosomes. In the absence of SWI/SNF, Gal4′s action also results in nucleosome removal and the activation of transcription, but both processes are significantly delayed. Addition of glucose to cells growing in galactose represses transcription. But if galactose remains present, Gal4 continues to work, recruiting SWI/SNF and maintaining the promoter nucleosome-free despite it being repressed. This requirement for galactose is obviated in a mutant in which Gal4 works constitutively. These results show how an activator's recruiting function can control chromatin structure both during gene activation and repression. Thus, both under activating and repressing conditions, the activator can recruit an enzymatic machine that removes promoter nucleosomes. Our results show that whereas promoter nucleosome removal invariably accompanies activation, reformation of nucleosomes is not required for repression. The finding that there are two routes to nucleosome removal and activation of transcription—one that requires the action of SWI/SNF recruited by the activator, and a slower one that does not—clarifies our understanding of the early events of gene activation, and in particular corrects earlier reports that SWI/SNF plays no role in GAL gene induction. Our finding that chromatin structure is irrelevant for repression as studied here—that is, repression sets in as efficiently whether or not promoter nucleosomes are allowed to reform—contradicts the widely held, but little tested, idea that nucleosomes are required for repression. These findings were made possible by our nucleosome occupancy assay. The assay, we believe, will prove useful in studying other outstanding issues in the field

Adult reversal of cognitive phenotypes in neurodevelopmental disorders

Recent findings in mice suggest that it is possible to reverse certain neurodevelopmental disorders in adults. Changes in development, previously thought to be irreparable in adults, were believed to underlie the neurological and psychiatric phenotypes of a range of common mental health problems with a clear developmental component. As a consequence, most researchers have focused their efforts on understanding the molecular and cellular processes that alter development with the hope that early intervention could prevent the emergent pathology. Unexpectedly, several different animal model studies published recently, including animal models of autism, suggest that it may be possible to reverse neurodevelopmental disorders in adults: Addressing the underlying molecular and cellular deficits in adults could in several cases dramatically improve the neurocognitive phenotypes in these animal models. The findings reviewed here provide hope to millions of individuals afflicted with a wide range of neurodevelopmental disorders, including autism, since they suggest that it may be possible to treat or even cure them in adults

The need for focused, hard X-ray investigations of the Sun

Understanding the nature of energetic particles in the solar atmosphere is one of the most important outstanding problems in heliophysics. Flare-accelerated particles compose a huge fraction of the flare energy budget; they have large influences on how events develop; they are an important source of high-energy particles found in the heliosphere; and they are the single most important corollary to other areas of high-energy astrophysics. Despite the importance of this area of study, this topic has in the past decade received only a small fraction of the resources necessary for a full investigation. For example, NASA has selected no new Explorer-class instrument in the past two decades that is capable of examining this topic. The advances that are currently being made in understanding flare-accelerated electrons are largely undertaken with data from EOVSA (NSF), STIX (ESA), and NuSTAR (NASA Astrophysics). This is despite the inclusion in the previous Heliophysics decadal survey of the FOXSI concept as part of the SEE2020 mission, and also despite NASA's having invested heavily in readying the technology for such an instrument via four flights of the FOXSI sounding rocket experiment. Due to that investment, the instrumentation stands ready to implement a hard X-ray mission to investigate flare-accelerated electrons. This white paper describes the scientific motivation for why this venture should be undertaken soon.Comment: White paper submitted to the Decadal Survey for Solar and Space Physics (Heliophysics) 2024-2033; 15 pages, 5 figure

High-energy Neutrino Astronomy: The Cosmic Ray Connection

This is a review of neutrino astronomy anchored to the observational fact that Nature accelerates protons and photons to energies in excess of $10^{20}$ and $10^{13}$ eV, respectively. Although the discovery of cosmic rays dates back close to a century, we do not know how and where they are accelerated. Basic elementary-particle physics dictates a universal upper limit on their energy of $5\times10^{19}$ eV, the so-called Greisen-Kuzmin-Zatsepin cutoff; however, particles in excess of this energy have been observed by all experiments, adding one more puzzle to the cosmic ray mystery. Mystery is fertile ground for progress: we will review the facts as well as the speculations about the sources including gamma ray bursts, blazars and top-down scenarios. The important conclusion is that, independently of the specific blueprint of the source, it takes a kilometer-scale neutrino observatory to detect the neutrino beam associated with the highest energy cosmic rays and gamma rays. We also briefly review the ongoing efforts to commission such instrumentation.Comment: 83 pages, 18 figures, submitted to Reports on Progress in Physic

Uncovering the complex genetics of human temperament

Experimental studies of learning suggest that human temperament may depend on the molecular mechanisms for associative conditioning, which are highly conserved in animals. The main genetic pathways for associative conditioning are known in experimental animals, but have not been identified in prior genome-wide association studies (GWAS) of human temperament. We used a data-driven machine learning method for GWAS to uncover the complex genotypic-phenotypic networks and environmental interactions related to human temperament. In a discovery sample of 2149 healthy Finns, we identified sets of single-nucleotide polymorphisms (SNPs) that cluster within particular individuals (i.e., SNP sets) regardless of phenotype. Second, we identified 3 clusters of people with distinct temperament profiles measured by the Temperament and Character Inventory regardless of genotype. Third, we found 51 SNP sets that identified 736 gene loci and were significantly associated with temperament. The identified genes were enriched in pathways activated by associative conditioning in animals, including the ERK, PI3K, and PKC pathways. 74% of the identified genes were unique to a specific temperament profile. Environmental influences measured in childhood and adulthood had small but significant effects. We confirmed the replicability of the 51 Finnish SNP sets in healthy Korean (90%) and German samples (89%), as well as their associations with temperament. The identified SNPs explained nearly all the heritability expected in each sample (37-53%) despite variable cultures and environments. We conclude that human temperament is strongly influenced by more than 700 genes that modulate associative conditioning by molecular processes for synaptic plasticity and long-term memory.Peer reviewe

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead