Susceptibility of beta 2-microglobulin-deficient mice to Trypanosoma cruzi infection.

The beta 2-microglobulin (beta 2m) protein associates with the products of the class I major histocompatibility (MHC) loci; this combination functions in the thymic development of and antigen presentation to CD8+ T cells. Mice in which the beta 2m gene has been disrupted by homologous recombination fail to express class I MHC gene products, and therefore lack CD8+ T cells and measurable cytotoxic T-cell responses. However, beta 2m- mice appear to have normal development of both CD4+ alpha/beta T-cell receptor (TCR+) and gamma/delta TCR+ T cells and are not overtly more susceptible than beta 2m+ mice to potential environmental agents of infection or to experimental viral infection. Here we show that beta 2m- mice suffer high parasitaemias and early death when infected with the obligate cytoplasmic protozoan parasite Trypanosoma cruzi. Despite this increased susceptibility, the beta 2m- mice are more responsive than their beta 2m+ littermates in terms of lymphokine production, making higher levels of both interleukin-2 and interferon-gamma in response to mitogen stimulation. In addition, the beta 2m- mice show essentially no inflammatory response in parasite-infected tissues. These results confirm previous experiments on mice depleted of CD8+ cells using antibody treatment in demonstrating the importance of CD8+ T cells in immune protection in T. cruzi infection. They also implicate CD8+ T cells and/or class I MHC molecules in regulation of lymphokine production and recruitment of inflammatory cells.     

The effect of migration on local adaptation in a coevolving host-parasite system

Antagonistic coevolution between hosts and parasites in spatially structured populations can result in local adaptation of parasites; that is, the greater infectivity of local parasites than foreign parasites on local hosts. Such parasite specialization on local hosts has implications for human health and agriculture. By contrast with classic single-species population-genetic models, theory indicates that parasite migration between subpopulations might increase parasite local adaptation, as long as migration does not completely homogenize populations. To test this hypothesis we developed a system-specific mathematical model and then coevolved replicate populations of the bacterium Pseudomonas fluorescens and a parasitic bacteriophage with parasite only, with host only or with no migration. Here we show that patterns of local adaptation have considerable temporal and spatial variation and that, in the absence of migration, parasites tend to be locally maladapted. However, in accord with our model, parasite migration results in parasite local adaptation, but host migration alone has no significant effect.     

Lamprey-like gills in a gnathostome-related Devonian jawless vertebrate

So far, the Palaeozoic fossil jawless vertebrates have not provided any direct evidence for the organization of the gills, apart from vague impressions--supposedly left by gill filaments--on the bony surface of the gill chamber in certain armoured forms or 'ostracoderms' (for example, osteostracans and heterostracans). The latter are currently regarded as more closely related to the living jawed vertebrates (crown gnathostomes) than to the living jawless vertebrates (hagfish and lampreys, or cyclostomes). Here we report the first direct evidence for the position of the gill filaments--possibly supported by gill rays--enclosed by gill pouches in a 370-million year (Myr)-old jawless vertebrate, Endeiolepis, from the Late Devonian fossil fish site of Miguasha, Quebec, Canada. This extinct jawless fish has much the same gill organization as living lampreys, although it possesses an unusually large number of gill pouches--a condition unlike that in any extant vertebrates and that raises questions about gill development. Endeiolepis is currently regarded as a close relative of anaspids, a group of 410-430-Myr-old 'ostracoderms'. Assuming that current vertebrate phylogeny is correct, this discovery demonstrates that pouches enclosing the gills are primitive for vertebrates, but have been subsequently lost in jawed vertebrates.     

Algorithms for ℓ<Subscript>1</Subscript>-Embeddability and Related Problems

Assouad has shown that a real-valued distance d = (d_ij)_{1 ≤ i < j ≤ n} is isometrically embeddable in ℓ₁space if and only if it belongs to the cut cone on n points. Determining if this condition holds is NP-complete. We use Assouad's result in a constructive column generation algorithm for ℓ₁-embeddability. The subproblem is an unconstrained 0-1 quadratic program, solved by Tabu Search and Variable Neighborhood Search heuristics as well as by an exact enumerative algorithm. Computational results are reported. Several ways to approximate a distance which is not ℓ₁-embeddable by another one which is are also studied.     

Replication fork movement sets chromatin loop size and origin choice in mammalian cells

Genome stability requires one, and only one, DNA duplication at each S phase. The mechanisms preventing origin firing on newly replicated DNA are well documented, but much less is known about the mechanisms controlling the spacing of initiation events(2,3), namely the completion of DNA replication. Here we show that origin use in Chinese hamster cells depends on both the movement of the replication forks and the organization of chromatin loops. We found that slowing the replication speed triggers the recruitment of latent origins within minutes, allowing the completion of S phase in a timely fashion. When slowly replicating cells are shifted to conditions of fast fork progression, although the decrease in the overall number of active origins occurs within 2 h, the cells still have to go through a complete cell cycle before the efficiency specific to each origin is restored. We observed a strict correlation between replication speed during a given S phase and the size of chromatin loops in the next G1 phase. Furthermore, we found that origins located at or near sites of anchorage of chromatin loops in G1 are activated preferentially in the following S phase. These data suggest a mechanism of origin programming in which replication speed determines the spacing of anchorage regions of chromatin loops, that, in turn, controls the choice of initiation sites.     

The CRISPR/Cas bacterial immune system cleaves bacteriophage and plasmid DNA

Bacteria and Archaea have developed several defence strategies against foreign nucleic acids such as viral genomes and plasmids. Among them, clustered regularly interspaced short palindromic repeats (CRISPR) loci together with cas (CRISPR-associated) genes form the CRISPR/Cas immune system, which involves partially palindromic repeats separated by short stretches of DNA called spacers, acquired from extrachromosomal elements. It was recently demonstrated that these variable loci can incorporate spacers from infecting bacteriophages and then provide immunity against subsequent bacteriophage infections in a sequence-specific manner. Here we show that the Streptococcus thermophilus CRISPR1/Cas system can also naturally acquire spacers from a self-replicating plasmid containing an antibiotic-resistance gene, leading to plasmid loss. Acquired spacers that match antibiotic-resistance genes provide a novel means to naturally select bacteria that cannot uptake and disseminate such genes. We also provide in vivo evidence that the CRISPR1/Cas system specifically cleaves plasmid and bacteriophage double-stranded DNA within the proto-spacer, at specific sites. Our data show that the CRISPR/Cas immune system is remarkably adapted to cleave invading DNA rapidly and has the potential for exploitation to generate safer microbial strains.