The genetics of health

Recent experience with several high-profile drugs demonstrates the great challenges in developing effective and safe therapeutics. A complementary approach to the popular paradigm of disease genetics is based on inherited factors that reduce the incidence and severity of disease among individuals who are genetically predisposed to disease. We propose testing specifically for modifier genes and protective alleles among at-risk individuals and studying the efficacy of therapeutics based on the genetics of health.     

Testing for the usefulness of forecasts

Ashley (Journal of Forecasting 1983; 2 (3): 211–223) proposes a criterion (known as Ashley's index) to judge whether the external macroeconomic variables are well forecast to serve as explanatory variables in forecasting models, which is crucial for policy makers. In this article, we try to extend Ashley's work by providing three testing procedures, including a ratio‐based test, a difference‐based test, and the Bayesian approach. The Bayesian approach has the advantage of allowing the flexibility of adapting all possible information content within a decision‐making environment such as the change of variable's definition due to the evolving system of national accounts. We demonstrate the proposed methods by applying six macroeconomic forecasts in the Survey of Professional Forecasters. Researchers or practitioners can thus formally test whether the external information is helpful. Copyright © 2010 John Wiley & Sons, Ltd.     

Early development of the razorback sucker, Xyrauchen texanus (Abbott)

  Fertilized ova of razorback sucker, Xyrauchen texanus, were adhesive for 3 to 4 hours after fertilization. Cleavage was completed at 24 hours, gastrulation occurred at 34 hours, and blood circulation was established at 117 hours. Hatching occurred from 5.2 to 5.5 days after fertilization. Larvae were from 6.8 to 7.3 mm TL at hatching. Yolk was assimilated at 13 days (10 mm TL). All fins were formed and had ossified rays at 64 days (27 mm TL). The unique nuchal keel appeared about 200 days after fertilization.     

Larger ectoparasites of the Idaho ground squirrel ( Spermophilus brunneus )

We sampled both subspecies of the Idaho ground squirrel ( Spermophilus brunneus ) to document the larger ectoparasites of this rare endemic. S. b. brunneus was host (+ = new host record, ? = new Idaho record) to 4 flea species ( Neopsylla inopina + , Oropsylla idahoensis + , O. tuberculata , and Thrassis pandorae +), 1 tick ( Ixodes sculptus +), and an eyeworm (Nematoda: Rhabditis orbitalis ? + , also 1st records from Seiuridae); S. b. endemicus was host to a louse species ( Neohaematopinus laeviusculus +), 5 flea taxa ( Rhadinopsylla sp. + , O. t. tuberculata, Thrassis f. francisi + , T. f. barnest + , and T. f. rockwoodi ), and a mite ( Androlaelaps fahrenholzi +). Spermophilus brunneus had fewer known ectoparasite species than other congeners. Although all of their parasites had many other hosts, S. b. endemicus and S. b. brunneus shared only a single parasite species in common, whereas all but one of their ectoparasites also occurred on the closely related Townsend's ground squirrel ( S. townsendii ). The proportion of parasitized individuals and the parasite loads per individual were significantly lower in S. b. brunneus , which lives in small, isolated populations, than in S. b. endemicus , which has larger, less fragmented populations, suggesting a relationship between host population structure, parasite loads, and parasite species diversity. All but one of the flea species have been linked to plague transmission.     

Visualization of subcellular NAD pools and intra-organellar protein localization by poly-ADP-ribose formation

Poly-ADP-ribose polymerases (PARPs) use NAD⁺ as substrate to generate polymers of ADP-ribose. We targeted the catalytic domain of human PARP1 as molecular NAD⁺ detector into cellular organelles. Immunochemical detection of polymers demonstrated distinct subcellular NAD⁺ pools in mitochondria, peroxisomes and, surprisingly, in the endoplasmic reticulum and the Golgi complex. Polymers did not accumulate within the mitochondrial intermembrane space or the cytosol. We demonstrate the suitability of this compartment-specific NAD⁺ and poly-ADP-ribose turnover to establish intra-organellar protein localization. For overexpressed proteins, genetically endowed with PARP activity, detection of polymers indicates segregation from the cytosol and consequently intra-organellar residence. In mitochondria, polymer build-up reveals matrix localization of the PARP fusion protein. Compared to presently used fusion tags for subcellular protein localization, these are substantial improvements in resolution. We thus established a novel molecular tool applicable for studies of subcellular NAD metabolism and protein localization.     

HIV-1 superinfection despite broad CD8+ T-cell responses containing replication of the primary virus

Early treatment of acute HIV-1 infection followed by treatment interruptions has shown promise for enhancing immune control of infection. A subsequent loss of control, however, allows the correlates of protective immunity to be assessed. Here we show that sudden breakthrough of plasma viraemia occurred after prolonged immune containment in an individual infected with HIV-1 at a time when 25 distinct CD8+ T-cell epitopes in the viral proteins Gag, RT, Integrase, Env, Nef, Vpr, Vif and Rev were being targeted. Sequencing of the virus in plasma and cells showed that superinfection with a second clade-B virus was coincident with the loss of immune control. This sudden increase in viraemia was associated with a decline in half of the CD8+ T-cell responses. The declining CD8+ T-cell responses were coupled with sequence changes relative to the initial virus that resulted in impaired recognition. Our data show that HIV-1 superinfection can occur in the setting of a strong and broadly directed virus-specific CD8+ T-cell response. The lack of cross-protective immunity for closely related HIV-1 strains, despite persistent recognition of multiple CD8 epitopes, has important implications for public health and vaccine development.     

Autoregressive gamma processes

We introduce a class of autoregressive gamma processes with conditional distributions from the family of noncentred gamma (up to a scale factor). The paper provides the stationarity and ergodicity conditions for ARG processes of any autoregressive order p, including long memory, and closed‐form expressions of conditional moments. The nonlinear state space representation of an ARG process is used to derive the filtering, smoothing and forecasting algorithms. The paper also presents estimation and inference methods, illustrated by an application to interquote durations data on an infrequently traded stock listed on the Toronto Stock Exchange (TSX). Copyright © 2006 John Wiley & Sons, Ltd.     

Sur l'histoire du théorème fondamental de l'algèbre: théorie des équations et calcul intégral

Sans résumé Mémoire présenté par U. Bottazzini