Multigenic control of Listeria monocytogenes susceptibility in mice

We have used a novel quantitative trait locus model to study the genetics of survival of F2 progeny of susceptible BALB/cByJ and resistant C57BL/6ByJ mice that have been infected with Listeria monocytogenes. This allowed us to map modifiers of L. monocytogenes susceptibility to chromosomes 5 and 13.     

Vitamin A controls epithelial/mesenchymal interactions through Ret expression

Mutations or rearrangements in the gene encoding the receptor tyrosine kinase RET result in Hirschsprung disease, cancer and renal malformations. The standard model of renal development involves reciprocal signaling between the ureteric bud epithelium, inducing metanephric mesenchyme to differentiate into nephrons, and metanephric mesenchyme, inducing the ureteric bud to grow and branch. RET and GDNF (a RET ligand) are essential mediators of these epithelial-mesenchymal interactions. Vitamin A deficiency has been associated with widespread embryonic abnormalities, including renal malformations. The vitamin A signal is transduced by nuclear retinoic acid receptors (RARs). We previously showed that two RAR genes, Rara and Rarb2, were colocalized in stromal mesenchyme, a third renal cell type, where their deletion led to altered stromal cell patterning, impaired ureteric bud growth and downregulation of Ret in the ureteric bud. Here we demonstrate that forced expression of Ret in mice deficient for both Rara and Rarb2 (Rara(-/-)Rarb2(-/-)) genetically rescues renal development, restoring ureteric bud growth and stromal cell patterning. Our studies indicate the presence of a new reciprocal signaling loop between the ureteric bud epithelium and the stromal mesenchyme, dependent on Ret and vitamin A. In the first part of the loop, vitamin-A-dependent signals secreted by stromal cells control Ret expression in the ureteric bud. In the second part of the loop, ureteric bud signals dependent on Ret control stromal cell patterning.     

High-resolution haplotype structure in the human genome

Linkage disequilibrium (LD) analysis is traditionally based on individual genetic markers and often yields an erratic, non-monotonic picture, because the power to detect allelic associations depends on specific properties of each marker, such as frequency and population history. Ideally, LD analysis should be based directly on the underlying haplotype structure of the human genome, but this structure has remained poorly understood. Here we report a high-resolution analysis of the haplotype structure across 500 kilobases on chromosome 5q31 using 103 single-nucleotide polymorphisms (SNPs) in a European-derived population. The results show a picture of discrete haplotype blocks (of tens to hundreds of kilobases), each with limited diversity punctuated by apparent sites of recombination. In addition, we develop an analytical model for LD mapping based on such haplotype blocks. If our observed structure is general (and published data suggest that it may be), it offers a coherent framework for creating a haplotype map of the human genome.     

Culture in low levels of oxygen enhances in vitro proliferation potential of satellite cells from old skeletal muscles

The proliferation ability of satellite cells (considered the 'stem cells' of mature myofibers) declines with increasing age when cultured under standard cell culture conditions of 21% oxygen. However, actual oxygen levels in the intact myofiber in vivo are an order of magnitude lower. No studies to date have addressed the issue of whether culturing satellite cells from old muscles under more 'physiologic' conditions would enhance their proliferation and/or differentiation ability. Therefore, we analyzed satellite cells derived from 31-month-old rats in standard cultures with 21% O₂ and in lowered (∼3%) O₂. Under the lowered O₂ conditions, we noted a remarkable increase in the percentage of large-sized colonies, activation of cell cycle progression factors, phosphorylation of Akt, and downregulation of the cell cycle inhibitor p27^Kip1. These data suggest that lower O₂ levels provide a milieu that stimulates proliferation by allowing continued cell cycle progression, to result ultimately in the enhanced in vitro replicative life span of the old satellite cells. Such a method therefore provides an improved means for the ex vivo generation of progenitor satellite cell populations for potential therapeutic stem cell transplantation. Received 20 April 2001; received after revision 28 May 2001; accepted 31 May 2001     

An abundance of X-linked genes expressed in spermatogonia

Spermatogonia are the self-renewing, mitotic germ cells of the testis from which sperm arise by means of the differentiation pathway known as spermatogenesis. By contrast with hematopoietic and other mammalian stem-cell populations, which have been subjects of intense molecular genetic investigation, spermatogonia have remained largely unexplored at the molecular level. Here we describe a systematic search for genes expressed in mouse spermatogonia, but not in somatic tissues. We identified 25 genes (19 of which are novel) that are expressed in only male germ cells. Of the 25 genes, 3 are Y-linked and 10 are X-linked. If these genes had been distributed randomly in the genome, one would have expected zero to two of the genes to be X-linked. Our findings indicate that the X chromosome has a predominant role in pre-meiotic stages of mammalian spermatogenesis. We hypothesize that the X chromosome acquired this prominent role in male germ-cell development as it evolved from an ordinary, unspecialized autosome.     

Noise to order

Patterns in natural systems abound, from the stripes on a zebra to ripples in a riverbed. In many of these systems, the appearance of an ordered state is not unexpected as the outcome of an underlying ordered process. Thus crystal growth, honeycomb manufacture and floret evolution generate regular and predictable patterns. Intrinsically noisy and disordered processes such as thermal fluctuations or mechanically randomized scattering generate surprisingly similar patterns. Here we discuss some of the underlying mechanisms believed to be at the heart of these similarities.     

Electrical spin injection and accumulation at room temperature in an all-metal mesoscopic spin valve

Finding a means to generate, control and use spin-polarized currents represents an important challenge for spin-based electronics, or 'spintronics'. Spin currents and the associated phenomenon of spin accumulation can be realized by driving a current from a ferromagnetic electrode into a non-magnetic metal or semiconductor. This was first demonstrated over 15 years ago in a spin injection experiment on a single crystal aluminium bar at temperatures below 77 K. Recent experiments have demonstrated successful optical detection of spin injection in semiconductors, using either optical injection by circularly polarized light or electrical injection from a magnetic semiconductor. However, it has not been possible to achieve fully electrical spin injection and detection at room temperature. Here we report room-temperature electrical injection and detection of spin currents and observe spin accumulation in an all-metal lateral mesoscopic spin valve, where ferromagnetic electrodes are used to drive a spin-polarized current into crossed copper strips. We anticipate that larger signals should be obtainable by optimizing the choice of materials and device geometry.     

New hominin genus from eastern Africa shows diverse middle Pliocene lineages

Most interpretations of early hominin phylogeny recognize a single early to middle Pliocene ancestral lineage, best represented by Australopithecus afarensis, which gave rise to a radiation of taxa in the late Pliocene. Here we report on new fossils discovered west of Lake Turkana, Kenya, which differ markedly from those of contemporary A. afarensis, indicating that hominin taxonomic diversity extended back, well into the middle Pliocene. A 3.5 Myr-old cranium, showing a unique combination of derived facial and primitive neurocranial features, is assigned to a new genus of hominin. These findings point to an early diet-driven adaptive radiation, provide new insight on the association of hominin craniodental features, and have implications for our understanding of Plio-Pleistocene hominin phylogeny.     

Enhancement of the high-magnetic-field critical current density of superconducting MgB2 by proton irradiation

Magnesium diboride, MgB2, has a relatively high superconducting transition temperature, placing it between the families of low- and high-temperature (copper oxide based) superconductors. Supercurrent flow in MgB2 is unhindered by grain boundaries, making it potentially attractive for technological applications in the temperature range 20-30 K. But in the bulk material, the critical current density (Jc) drops rapidly with increasing magnetic field strength. The magnitude and field dependence of the critical current are related to the presence of structural defects that can 'pin' the quantized magnetic vortices that permeate the material, and a lack of natural defects in MgB2 may be responsible for the rapid decline of Jc with increasing field strength. Here we show that modest levels of atomic disorder induced by proton irradiation enhance the pinning of vortices, thereby significantly increasing Jc at high field strengths. We anticipate that either chemical doping or mechanical processing should generate similar levels of disorder, and so achieve performance that is technologically attractive in an economically viable way.