Evidence for several waves of global transmission in the seventh cholera pandemic

Vibrio cholerae is a globally important pathogen that is endemic in many areas of the world and causes 3-5 million reported cases of cholera every year. Historically, there have been seven acknowledged cholera pandemics; recent outbreaks in Zimbabwe and Haiti are included in the seventh and ongoing pandemic. Only isolates in serogroup O1 (consisting of two biotypes known as 'classical' and 'El Tor') and the derivative O139 can cause epidemic cholera. It is believed that the first six cholera pandemics were caused by the classical biotype, but El Tor has subsequently spread globally and replaced the classical biotype in the current pandemic. Detailed molecular epidemiological mapping of cholera has been compromised by a reliance on sub-genomic regions such as mobile elements to infer relationships, making El Tor isolates associated with the seventh pandemic seem superficially diverse. To understand the underlying phylogeny of the lineage responsible for the current pandemic, we identified high-resolution markers (single nucleotide polymorphisms; SNPs) in 154 whole-genome sequences of globally and temporally representative V. cholerae isolates. Using this phylogeny, we show here that the seventh pandemic has spread from the Bay of Bengal in at least three independent but overlapping waves with a common ancestor in the 1950s, and identify several transcontinental transmission events. Additionally, we show how the acquisition of the SXT family of antibiotic resistance elements has shaped pandemic spread, and show that this family was first acquired at least ten years before its discovery in V. cholerae.     

Forecasts for leverage heterogeneous autoregressive models with jumps and other covariates

For leverage heterogeneous autoregressive (LHAR) models with jumps and other covariates, called LHARX models, multistep forecasts are derived. Some optimal properties of forecasts in terms of conditional volatilities are discussed, which tells us to model conditional volatility for return but not for the LHARX regression error and other covariates. Forecast standard errors are constructed for which we need to model conditional volatilities both for return and for LHAR regression error and other blue covariates. The proposed methods are well illustrated by forecast analysis for the realized volatilities of the US stock price indexes: the S&P 500, the NASDAQ, the DJIA, and the RUSSELL indexes.     

Misspecified prediction for time series

Let {X_t} be a stationary process with spectral density g(λ).It is often that the true structure g(λ) is not completely specified. This paper discusses the problem of misspecified prediction when a conjectured spectral density f_θ(λ), θ∈Θ, is fitted to g(λ). Then, constructing the best linear predictor based on f_θ(λ), we can evaluate the prediction error M(θ). Since θ is unknown we estimate it by a quasi‐MLE . The second‐order asymptotic approximation of is given. This result is extended to the case when X_t contains some trend, i.e. a time series regression model. These results are very general. Furthermore we evaluate the second‐order asymptotic approximation of for a time series regression model having a long‐memory residual process with the true spectral density g(λ). Since the general formulae of the approximated prediction error are complicated, we provide some numerical examples. Then we illuminate unexpected effects from the misspecification of spectra. Copyright © 2001 John Wiley & Sons, Ltd.     

Aberrant CFTR-dependent HCO3- transport in mutations associated with cystic fibrosis

Cystic fibrosis (CF) is a disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). Initially, Cl- conductance in the sweat duct was discovered to be impaired in CF, a finding that has been extended to all CFTR-expressing cells. Subsequent cloning of the gene showed that CFTR functions as a cyclic-AMP-regulated Cl- channel; and some CF-causing mutations inhibit CFTR Cl- channel activity. The identification of additional CF-causing mutants with normal Cl- channel activity indicates, however, that other CFTR-dependent processes contribute to the disease. Indeed, CFTR regulates other transporters, including Cl(-)-coupled HCO3- transport. Alkaline fluids are secreted by normal tissues, whereas acidic fluids are secreted by mutant CFTR-expressing tissues, indicating the importance of this activity. HCO3- and pH affect mucin viscosity and bacterial binding. We have examined Cl(-)-coupled HCO3- transport by CFTR mutants that retain substantial or normal Cl- channel activity. Here we show that mutants reported to be associated with CF with pancreatic insufficiency do not support HCO3- transport, and those associated with pancreatic sufficiency show reduced HCO3- transport. Our findings demonstrate the importance of HCO3- transport in the function of secretory epithelia and in CF.     

Extinction-induced upregulation in AMPA receptors reduces cocaine-seeking behaviour

Cocaine addiction is thought to involve persistent neurobiological changes that facilitate relapse to drug use despite efforts to abstain. But the propensity for relapse may be reduced by extinction training--a form of inhibitory learning that progressively reduces cocaine-seeking behaviour in the absence of cocaine reward. Here we show that extinction training during withdrawal from chronic cocaine self-administration induces experience-dependent increases in the GluR1 and GluR2/3 subunits of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate) glutamate receptors in the nucleus accumbens shell, a brain region that is critically involved in cocaine reward. Increases in the GluR1 subunit are positively associated with the level of extinction achieved during training, suggesting that GluR1 may promote extinction of cocaine seeking. Indeed, viral-mediated overexpression of both GluR1 and GluR2 in nucleus accumbens shell neurons facilitates extinction of cocaine- but not sucrose-seeking responses. A single extinction training session, when conducted during GluR subunit overexpression, attenuates stress-induced relapse to cocaine seeking even after GluR overexpression declines. Our findings indicate that extinction-induced plasticity in AMPA receptors may facilitate control over cocaine seeking by restoring glutamatergic tone in the nucleus accumbens, and may reduce the propensity for relapse under stressful situations in prolonged abstinence.     

Inactivation of human glutamate dehydrogenase by aluminum

Aluminum inactivated glutamate dehydrogenase (GDH) by a pseudo-first-order reaction at micromolar concentrations. A double-reciprocal plot gave a straight line with a k_inact of 2.7 min^-1 and indicated the presence of a binding step prior to inactivation. The inactivation was strictly pH dependent and a marked increase in sensitivity to aluminum was observed as the pH decreased. At a pH higher than 8.5, no inactivation was observed. The completely inactivated GDH contained 2 mol of aluminum per mole of enzyme subunit monomer. When preincubated with enzyme, several chelators such as citrate, NaF, N-(2-hydroxyethyl) ethylenediaminetriacetic acid or ethylenediaminetriacetic acid efficiently protected the enzyme against the aluminum inactivation. In a related experiment, only citrate and NaF released the aluminum from the completely inactivated aluminum-enzyme complex and fully recovered the enzyme activity. Ferritin, NADP⁺, or nerve growth factor did not show any effects on the recovery of the aluminum-inactivated GDH activity. The dissociation constant for the aluminum-enzyme complex was calculated to be 5.3 M. Although aluminum has been known to form a complex with nucleotides, no such effects were observed in the inactivation of GDH by aluminum as determined using GDHs mutated at the ADP-binding site, NAD⁺-binding site or GTP-binding site. Circular dichroism studies showed that the binding of aluminum to the enzyme induced a decrease in helices and sheets and an increase in random coil. Therefore, inactivation of GDH by aluminum is suggested to be due to the conformational change induced by aluminum binding. These results suggest a possibility that aluminum-induced alterations in enzymes of the glutamate system may be one of the causes of aluminum-induced neurotoxicity.Received 25 July 2003; received after revision 27 August 2003; accepted 15 September 2003     

Rate of molecular evolution of the seminal protein gene SEMG2 correlates with levels of female promiscuity

Postcopulatory sperm competition is a key aspect of sexual selection and is believed to drive the rapid evolution of both reproductive physiology and reproduction-related genes. It is well-established that mating behavior determines the intensity of sperm competition, with polyandry (i.e., female promiscuity) leading to fiercer sperm competition than monandry. Studies in mammals, particularly primates, showed that, owing to greater sperm competition, polyandrous taxa generally have physiological traits that make them better adapted for fertilization than monandrous species, including bigger testes, larger seminal vesicles, higher sperm counts, richer mitochondrial loading in sperm and more prominent semen coagulation. Here, we show that the degree of polyandry can also impact the dynamics of molecular evolution. Specifically, we show that the evolution of SEMG2, the gene encoding semenogelin II, a main structural component of semen coagulum, is accelerated in polyandrous primates relative to monandrous primates. Our study showcases the intimate relationship between sexual selection and the molecular evolution of reproductive genes.