Characterizing a first occurrence of bison deposits in southeastern Nevada

Late Holocene bison bones eroding from the badlands topography of Cathedral Gorge State Park in southeastern Nevada have been identified as the remains of Bison and date between approximately 400 and 850 years old. The bones were originally thought to be turn-of-the-century cattle and then early bison, so park personnel had need to solve this interpretive problem. A multidisciplinary team sought information on archaeology, geomorphology, paleontology, and paleoenvironment to document the 1st established occurrence of bison in this part of Nevada and to develop a hypothesis explaining their demise.     

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.     

Evolved structure of language shows lineage-specific trends in word-order universals

Languages vary widely but not without limit. The central goal of linguistics is to describe the diversity of human languages and explain the constraints on that diversity. Generative linguists following Chomsky have claimed that linguistic diversity must be constrained by innate parameters that are set as a child learns a language. In contrast, other linguists following Greenberg have claimed that there are statistical tendencies for co-occurrence of traits reflecting universal systems biases, rather than absolute constraints or parametric variation. Here we use computational phylogenetic methods to address the nature of constraints on linguistic diversity in an evolutionary framework. First, contrary to the generative account of parameter setting, we show that the evolution of only a few word-order features of languages are strongly correlated. Second, contrary to the Greenbergian generalizations, we show that most observed functional dependencies between traits are lineage-specific rather than universal tendencies. These findings support the view that-at least with respect to word order-cultural evolution is the primary factor that determines linguistic structure, with the current state of a linguistic system shaping and constraining future states.     

Local leukocyte mobilization in irradiated or cyclophosphamide-treated rats

Summary Sprague-Dawley rats made neutropenic by⁶⁰Co irradiation or cyclophosphamide treatment retained a limited capacity for mounting a local leukocyte mobilization (LLM) response. Rats irradiated with 700 rad⁶⁰Co lacked an LLM. Rats treated with 100 mg/kg cyclophosphamide showed no LLM following an initial low response when assayed originally.We wish to thank Mr Dane Walden for excellent technical assistance. This work was supported by Armed Forces Radiobiology Research Institute, Defense Nuclear Agency, under Research Work Unit MJ 60212. The views presented in this paper are those of the authors. No endorsement of the Defense Nuclear Agency has been given or should be inferred.     

Ultrastructural visualization of Cabot rings in pernicious anemia

Summary Using the ammoniacal silver stain, Cabot rings were identified in peripheral blood erythrocytes from patients with severe untreated pernicious anemia. Ultrastructural studies of these erythrocytes showed silver deposits in partial loops and figure-eight forms, indicating that arginine rich histone may be a prominent component of the Cabot ring.Supported in part by the Elizabeth Roodvoets Memorial Grant for Cancer Research of the American Cancer Society (No. CI-79) and by National Cancer Institute Grant USPHS No. CA 14428-02.     

Translating insights from the cancer genome into clinical practice

Cancer cells have diverse biological capabilities that are conferred by numerous genetic aberrations and epigenetic modifications. Today's powerful technologies are enabling these changes to the genome to be catalogued in detail. Tomorrow is likely to bring a complete atlas of the reversible and irreversible alterations that occur in individual cancers. The challenge now is to work out which molecular abnormalities contribute to cancer and which are simply 'noise' at the genomic and epigenomic levels. Distinguishing between these will aid in understanding how the aberrations in a cancer cell collaborate to drive pathophysiology. Past successes in converting information from genomic discoveries into clinical tools provide valuable lessons to guide the translation of emerging insights from the genome into clinical end points that can affect the practice of cancer medicine.     

A systematic, genome-wide, phenotype-driven mutagenesis programme for gene function studies in the mouse

As the human genome project approaches completion, the challenge for mammalian geneticists is to develop approaches for the systematic determination of mammalian gene function. Mouse mutagenesis will be a key element of studies of gene function. Phenotype-driven approaches using the chemical mutagen ethylnitrosourea (ENU) represent a potentially efficient route for the generation of large numbers of mutant mice that can be screened for novel phenotypes. The advantage of this approach is that, in assessing gene function, no a priori assumptions are made about the genes involved in any pathway. Phenotype-driven mutagenesis is thus an effective method for the identification of novel genes and pathways. We have undertaken a genome-wide, phenotype-driven screen for dominant mutations in the mouse. We generated and screened over 26,000 mice, and recovered some 500 new mouse mutants. Our work, along with the programme reported in the accompanying paper, has led to a substantial increase in the mouse mutant resource and represents a first step towards systematic studies of gene function in mammalian genetics.     

Regulation of pyruvate metabolism and human disease

Pyruvate is a keystone molecule critical for numerous aspects of eukaryotic and human metabolism. Pyruvate is the end-product of glycolysis, is derived from additional sources in the cellular cytoplasm, and is ultimately destined for transport into mitochondria as a master fuel input undergirding citric acid cycle carbon flux. In mitochondria, pyruvate drives ATP production by oxidative phosphorylation and multiple biosynthetic pathways intersecting the citric acid cycle. Mitochondrial pyruvate metabolism is regulated by many enzymes, including the recently discovered mitochondria pyruvate carrier, pyruvate dehydrogenase, and pyruvate carboxylase, to modulate overall pyruvate carbon flux. Mutations in any of the genes encoding for proteins regulating pyruvate metabolism may lead to disease. Numerous cases have been described. Aberrant pyruvate metabolism plays an especially prominent role in cancer, heart failure, and neurodegeneration. Because most major diseases involve aberrant metabolism, understanding and exploiting pyruvate carbon flux may yield novel treatments that enhance human health.