Frontal and stealth attack strategies in microbial pathogenesis

Interactions between microbes and human hosts can range from a benign, even symbiotic collaboration to a competition that may turn fatal--resulting in death of the host, the microbe or both. Despite advances that have been made over the past decades in understanding microbial pathogens, more people worldwide still die every year from infectious disease than from any other cause. This highlights the relevance of continuing to probe the mechanisms used by microorganisms to cause disease, and emphasizes the need for new model systems to advance our understanding of host-pathogen interactions.     

DNA sequence and analysis of human chromosome 9

Chromosome 9 is highly structurally polymorphic. It contains the largest autosomal block of heterochromatin, which is heteromorphic in 6-8% of humans, whereas pericentric inversions occur in more than 1% of the population. The finished euchromatic sequence of chromosome 9 comprises 109,044,351 base pairs and represents >99.6% of the region. Analysis of the sequence reveals many intra- and interchromosomal duplications, including segmental duplications adjacent to both the centromere and the large heterochromatic block. We have annotated 1,149 genes, including genes implicated in male-to-female sex reversal, cancer and neurodegenerative disease, and 426 pseudogenes. The chromosome contains the largest interferon gene cluster in the human genome. There is also a region of exceptionally high gene and G + C content including genes paralogous to those in the major histocompatibility complex. We have also detected recently duplicated genes that exhibit different rates of sequence divergence, presumably reflecting natural selection.     

VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche

The cellular and molecular mechanisms by which a tumour cell undergoes metastasis to a predetermined location are largely unknown. Here we demonstrate that bone marrow-derived haematopoietic progenitor cells that express vascular endothelial growth factor receptor 1 (VEGFR1; also known as Flt1) home to tumour-specific pre-metastatic sites and form cellular clusters before the arrival of tumour cells. Preventing VEGFR1 function using antibodies or by the removal of VEGFR1(+) cells from the bone marrow of wild-type mice abrogates the formation of these pre-metastatic clusters and prevents tumour metastasis, whereas reconstitution with selected Id3 (inhibitor of differentiation 3)-competent VEGFR1+ cells establishes cluster formation and tumour metastasis in Id3 knockout mice. We also show that VEGFR1+ cells express VLA-4 (also known as integrin alpha4beta1), and that tumour-specific growth factors upregulate fibronectin--a VLA-4 ligand--in resident fibroblasts, providing a permissive niche for incoming tumour cells. Conditioned media obtained from distinct tumour types with unique patterns of metastatic spread redirected fibronectin expression and cluster formation, thereby transforming the metastatic profile. These findings demonstrate a requirement for VEGFR1+ haematopoietic progenitors in the regulation of metastasis, and suggest that expression patterns of fibronectin and VEGFR1+VLA-4+ clusters dictate organ-specific tumour spread.     

Chromosome-wide distribution of haplotype blocks and the role of recombination hot spots

Recent studies of human populations suggest that the genome consists of chromosome segments that are ancestrally conserved ('haplotype blocks'; refs. 1-3) and have discrete boundaries defined by recombination hot spots. Using publicly available genetic markers, we have constructed a first-generation haplotype map of chromosome 19. As expected for this marker density, approximately one-third of the chromosome is encompassed within haplotype blocks. Evolutionary modeling of the data indicates that recombination hot spots are not required to explain most of the observed blocks, providing that marker ascertainment and the observed marker spacing are considered. In contrast, several long blocks are inconsistent with our evolutionary models, and different mechanisms could explain their origins.     

Heterozygous mutations of the kinesin KIF21A in congenital fibrosis of the extraocular muscles type 1 (CFEOM1)

Congenital fibrosis of the extraocular muscles type 1 (CFEOM1; OMIM #135700) is an autosomal dominant strabismus disorder associated with defects of the oculomotor nerve. We show that individuals with CFEOM1 harbor heterozygous missense mutations in a kinesin motor protein encoded by KIF21A. We identified six different mutations in 44 of 45 probands. The primary mutational hotspots are in the stalk domain, highlighting an important new role for KIF21A and its stalk in the formation of the oculomotor axis.     

An abundant population of small irregular satellites around Jupiter

Irregular satellites have eccentric orbits that can be highly inclined or even retrograde relative to the equatorial planes of their planets. These objects cannot have formed by circumplanetary accretion, unlike the regular satellites that follow uninclined, nearly circular and prograde orbits. Rather, they are probably products of early capture from heliocentric orbits. Although the capture mechanism remains uncertain, the study of irregular satellites provides a window on processes operating in the young Solar System. Families of irregular satellites recently have been discovered around Saturn (thirteen members, refs 6, 7), Uranus (six, ref. 8) and Neptune (three, ref. 9). Because Jupiter is closer than the other giant planets, searches for smaller and fainter irregular satellites can be made. Here we report the discovery of 23 new irregular satellites of Jupiter, so increasing the total known population to 32. There are five distinct satellite groups, each dominated by one relatively large body. The groups were most probably produced by collisional shattering of precursor objects after capture by Jupiter.