Bayesian modeling of skewed X inactivation in genetically diverse mice identifies a novel Xce allele associated with copy number changes

Female mammals are functional mosaics of their parental X-linked gene expression due to X chromosome inactivation (XCI). This process inactivates one copy of the X chromosome in each cell during embryogenesis and that state is maintained clonally through mitosis. In mice, the choice of which parental X chromosome remains active is determined by the X chromosome controlling element (Xce), which has been mapped to a 176-kb candidate interval. A series of functional Xce alleles has been characterized or inferred for classical inbred strains based on biased, or skewed, inactivation of the parental X chromosomes in crosses between strains. To further explore the function structure basis and location of the Xce, we measured allele-specific expression of X-linked genes in a large population of F1 females generated from Collaborative Cross (CC) strains. Using published sequence data and applying a Bayesian “Pólya urn” model of XCI skew, we report two major findings. First, inter-individual variability in XCI suggests mouse epiblasts contain on average 20–30 cells contributing to brain. Second, CC founder strain NOD/ShiLtJ has a novel and unique functional allele, Xce^g, that is the weakest in the Xce allelic series. Despite phylogenetic analysis confirming that NOD/ShiLtJ carries a haplotype almost identical to the well-characterized C57BL/6J (Xce^b), we observed unexpected patterns of XCI skewing in females carrying the NOD/ShiLtJ haplotype within the Xce. Copy number variation is common at the Xce locus and we conclude that the observed allelic series is a product of independent and recurring duplications shared between weak Xce alleles.     

Treadmill desks: A 1‐year prospective trial

Objective: Sedentariness is associated with weight gain and obesity. A treadmill desk is the combination of a standing desk and a treadmill that allow employees to work while walking at low speed. Design and Methods: The hypothesis was that a 1‐year intervention with treadmill desks is associated with an increase in employee daily physical activity (summation of all activity per minute) and a decrease in daily sedentary time (zero activity). Employees (n = 36; 25 women, 11 men) with sedentary jobs (87 ± 27 kg, BMI 29 ± 7 kg/m², n = 10 Lean BMI < 25 kg/m², n = 15 Overweight 25 < BMI < 30 kg/m², n = 11 Obese BMI > 30 kg/m²) volunteered to have their traditional desk replaced with a treadmill desk to promote physical activity for 1 year. Results: Daily physical activity (using accelerometers), work performance, body composition, and blood variables were measured at Baseline and 6 and 12 months after the treadmill desk intervention. Subjects who used the treadmill desk increased daily physical activity from baseline 3,353 ± 1,802 activity units (AU)/day to, at 6 months, 4,460 ± 2,376 AU/day (P < 0.001), and at 12 months, 4,205 ± 2,238 AU/day (P < 0.001). Access to the treadmill desks was associated with significant decreases in daily sedentary time (zero activity) from at baseline 1,020 ± 75 min/day to, at 6 months, 929 ± 84 min/day (P < 0.001), and at 12 months, 978 ± 95 min/day (P < 0.001). For the whole group, weight loss averaged 1.4 ± 3.3 kg (P < 0.05). Weight loss for obese subjects was 2.3 ± 3.5 kg (P < 0.03). Access to the treadmill desks was associated with increased daily physical activity compared to traditional chair‐based desks; their deployment was not associated with altered performance. For the 36 participants, fat mass did not change significantly, however, those who lost weight (n = 22) lost 3.4 ± 5.4 kg (P < 0.001) of fat mass. Weight loss was greatest in people with obesity. Conclusions: Access to treadmill desks may improve the health of office workers without affecting work performance.     

Apple 1-aminocyclopropane-1-carboxylate synthase in complex with the inhibitor L-aminoethoxyvinylglycine. Evidence for a ketimine intermediate

The 1.6-A crystal structure of the covalent ketimine complex of apple 1-aminocyclopropane-1-carboxylate (ACC) synthase with the potent inhibitor l-aminoethoxyvinylglycine (AVG) is described. ACC synthase catalyzes the committed step in the biosynthesis of ethylene, a plant hormone that is responsible for the initiation of fruit ripening and for regulating many other developmental processes. AVG is widely used in plant physiology studies to inhibit the activity of ACC synthase. The structural assignment is supported by the fact that the complex absorbs maximally at 341 nm. These results are not in accord with the recently reported crystal structure of the tomato ACC synthase AVG complex, which claims that the inhibitor only associates noncovalently. The rate constant for the association of AVG with apple ACC synthase was determined by stopped-flow spectrophotometry (2.1 x 10(5) m(-1) s(-1)) and by the rate of loss of enzyme activity (1.1 x 10(5) m(-1) s(-1)). The dissociation rate constant determined by activity recovery is 2.4 x 10(-6) s(-1). Thus, the calculated K(d) value is 10-20 pm.     

Spaceflight and development of immune responses

The NIH.R1 Space Shuttle experiment wasdesigned to study the effects of spaceflight on rodent development.Pregnant rats were flown on the Space Shuttle for 11 days, and pregnantcontrol rats were maintained in animal enclosure modules in aground-based chamber under conditions approximating those in flight.Additional controls were in standard housing. The effects of the flighton immunological parameters of dams, fetuses, and pups were determined. Blastogenesis of spleen cells in response to mitogen was inhibited inflown dams but was not inhibited in cells from their pups. Interferon- production by spleen cells showed a trend toward inhibition in flown dams but not in their pups. The response of bonemarrow cells to colony-stimulating factor showed a trend towardinhibition after spaceflight in dams, but the response of fetus and pupliver cells was not inhibited. Total serum IgG was not affected byspaceflight. None of the examined immune parameters that were alteredin rat dams after spaceflight was found to be altered in theiroffspring.

     

Potent and selective cyclohexyl-derived imidazopyrazine insulin-like growth factor 1 receptor inhibitors with in vivo efficacy

Preclinical and emerging clinical evidence suggests that inhibiting insulin-like growth factor 1 receptor (IGF-1R) signaling may offer a promising therapeutic strategy for the treatment of several types of cancer. This Letter describes the medicinal chemistry effort towards a series of 8-amino-imidazo[1,5-a]pyrazine derived inhibitors of IGF-1R which features a substituted quinoline moiety at the C1 position and a cyclohexyl linking moiety at the C3 position. Lead optimization efforts which included the optimization of structure-activity relationships and drug metabolism and pharmacokinetic properties led to the identification of compound 9m, a potent, selective and orally bioavailable inhibitor of IGF-1R with in vivo efficacy in an IGF-driven mouse xenograft model.     

The collaborative cross: a recombinant inbred mouse population for the systems genetic era

The mouse is the most extensively used mammalian model for biomedical and aging research, and an extensive catalogue of laboratory resources is available to support research using mice: classical inbred lines, genetically modified mice (knockouts, transgenics, and humanized mice), selectively bred lines, consomics, congenics, recombinant inbred panels, outbred and heterogeneous stocks, and an expanding set of wild-derived strains. However, these resources were not designed or intended to model the heterogeneous human population or for a systematic analysis of phenotypic effects due to random combinations of uniformly distributed natural variants. The Collaborative Cross (CC) is a large panel of recently established multiparental recombinant inbred mouse lines specifically designed to overcome the limitations of existing mouse genetic resources for analysis of phenotypes caused by combinatorial allele effects. The CC models the complexity of the human genome and supports analyses of common human diseases with complex etiologies originating through interactions between allele combinations and the environment. The CC is the only mammalian resource that has high and uniform genomewide genetic variation effectively randomized across a large, heterogeneous, and infinitely reproducible population. The CC supports data integration across environmental and biological perturbations and across space (different labs) and time.     

Evaluation of the HOOF-Print assay for typing <Emphasis Type="Italic">Brucella abortus</Emphasis> strains isolated from cattle in the United States: results with four performance criteria

Background  

A fundamental question that arises during epidemiological investigations of bacterial disease outbreaks is whether the outbreak strain is genetically related to a proposed index strain. Highly discriminating genetic markers for characterizing bacterial strains can help in clarifying the genetic relationships among strains. Under the auspices of the European Society of Clinical Microbiology and Infectious Diseases, the European Study Group for Epidemiological Markers (ESGEM) established guidelines for evaluating the performance of typing systems based of a number of criteria. Recently, HOOF-Print genotype analysis, a new method for typing Brucella abortus strains based on hypervariability at eight tandem repeat loci, was described. This paper evaluates the HOOF-Print assay by four of the criteria set out by the ESGEM: typeability, reproducibility, power of discrimination, and concordance with other typing methods.     

Roots in Corynaea (Balanophoraceae)

The tuberous base of the holoparasite Corynaea crassa (Balanophoraceae), unlike perhaps all other members of the family, bears numerous short, unbranched organs which are interpreted as vestigial roots.     

Provisioning of Public Health Can Be Designed to Anticipate Public Policy Responses

Public health policies can elicit strong responses from individuals. These responses can promote, reduce, and even reverse the expected benefits of the policies. Therefore, projections of individual responses to policy can be important ingredients in policy design. Yet our foresight of individual responses to public health investment remains limited. This paper formulates a population game describing the prevention of infectious disease transmission when community health depends on the interactions of individual and public investments. We compare three common relationships between public and individual investments and explain how each relationship alters policy responses and health outcomes. Our methods illustrate how identifying system interactions between nature and society can help us anticipate policy responses.