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1.  Pleiotropy constrains the evolution of protein but not regulatory sequences in a transcription regulatory network influencing complex social behaviors 
Frontiers in Genetics  2014;5:431.
It is increasingly apparent that genes and networks that influence complex behavior are evolutionary conserved, which is paradoxical considering that behavior is labile over evolutionary timescales. How does adaptive change in behavior arise if behavior is controlled by conserved, pleiotropic, and likely evolutionary constrained genes? Pleiotropy and connectedness are known to constrain the general rate of protein evolution, prompting some to suggest that the evolution of complex traits, including behavior, is fuelled by regulatory sequence evolution. However, we seldom have data on the strength of selection on mutations in coding and regulatory sequences, and this hinders our ability to study how pleiotropy influences coding and regulatory sequence evolution. Here we use population genomics to estimate the strength of selection on coding and regulatory mutations for a transcriptional regulatory network that influences complex behavior of honey bees. We found that replacement mutations in highly connected transcription factors and target genes experience significantly stronger negative selection relative to weakly connected transcription factors and targets. Adaptively evolving proteins were significantly more likely to reside at the periphery of the regulatory network, while proteins with signs of negative selection were near the core of the network. Interestingly, connectedness and network structure had minimal influence on the strength of selection on putative regulatory sequences for both transcription factors and their targets. Our study indicates that adaptive evolution of complex behavior can arise because of positive selection on protein-coding mutations in peripheral genes, and on regulatory sequence mutations in both transcription factors and their targets throughout the network.
PMCID: PMC4275039  PMID: 25566318
Apis mellifera; network hubs; natural selection; evo devo; social evolution
2.  Evolution of recombination and genome structure in eusocial insects 
Eusocial Hymenoptera, such as the European honey bee, Apis mellifera, have the highest recombination rates of multicellular animals.1 Recently, we showed2 that a side-effect of recombination in the honey bee, GC biased gene conversion (bGC), helps maintain the unusual bimodal GC-content distribution of the bee genome by increasing GC-content in high recombination areas while low recombination areas are losing GC-content because of biased AT mutations and low rates of bGC. Although the very high recombination rate of A. mellifera makes GC-content evolution easier to study, the pattern is consistent with results found in many other species including mammals and yeast.3 Also consistent across phyla is the association of higher genetic diversity and divergence with high GC and high recombination areas.4,5 Finally, we showed that genes overexpressed in the brains of workers cluster in GC-rich genomic areas with the highest rates of recombination and molecular evolution.2 In this Addendum we present a conceptual model of how eusociality and high recombination rates may co-evolve.
PMCID: PMC3609837  PMID: 23748924
recombination; eusocial; honey bee; Apis; biased gene conversion; indirect genetic effects; drift; effective population size
3.  Confirmation diagnosis of influenza A(H1N1)2009 by Belgian sentinel laboratories during the epidemic phase 
Archives of Public Health  2010;68(2):76-82.
PMCID: PMC3463024
Influenza; A(H1N1)pandemic; epidemiology; laboratory diagnosis
4.  Improvement of gait by chronic, high doses of methylphenidate in patients with advanced Parkinson's disease 
Therapeutic management of gait disorders in patients with advanced Parkinson's disease (PD) can sometimes be disappointing, since dopaminergic drug treatments and subthalamic nucleus (STN) stimulation are more effective for limb‐related parkinsonian signs than for gait disorders. Gait disorders could also be partly related to norepinephrine system impairment, and the pharmacological modulation of both dopamine and norepinephrine pathways could potentially improve the symptomatology.
To assess the clinical value of chronic, high doses of methylphenidate (MPD) in patients with PD having gait disorders, despite their use of optimal dopaminergic doses and STN stimulation parameters.
Efficacy was blindly assessed on video for 17 patients in the absence of l‐dopa and again after acute administration of the drug, both before and after a 3‐month course of MPD, using a Stand–Walk–Sit (SWS) Test, the Tinetti Scale, the Unified Parkinson's Disease Rating Scale (UPDRS) part III score and the Dyskinesia Rating Scale.
An improvement was observed in the number of steps and time in the SWS Test, the number of freezing episodes, the Tinetti Scale score and the UPDRS part III score in the absence of l‐dopa after 3 months of taking MPD. The l‐dopa‐induced improvement in these various scores was also stronger after the 3‐month course of MPD than before. The Epworth Sleepiness Scale score fell dramatically in all patients. No significant induction of adverse effects was found.
Chronic, high doses of MPD improved gait and motor symptoms in the absence of l‐dopa and increased the intensity of response of these symptoms to l‐dopa in a population with advanced PD.
PMCID: PMC2117830  PMID: 17098845
5.  The Drosophila foraging Gene Mediates Adult Plasticity and Gene–Environment Interactions in Behaviour, Metabolites, and Gene Expression in Response to Food Deprivation 
PLoS Genetics  2009;5(8):e1000609.
Nutrition is known to interact with genotype in human metabolic syndromes, obesity, and diabetes, and also in Drosophila metabolism. Plasticity in metabolic responses, such as changes in body fat or blood sugar in response to changes in dietary alterations, may also be affected by genotype. Here we show that variants of the foraging (for) gene in Drosophila melanogaster affect the response to food deprivation in a large suite of adult phenotypes by measuring gene by environment interactions (GEI) in a suite of food-related traits. for affects body fat, carbohydrates, food-leaving behavior, metabolite, and gene expression levels in response to food deprivation. This results in broad patterns of metabolic, genomic, and behavioral gene by environment interactions (GEI), in part by interaction with the insulin signaling pathway. Our results show that a single gene that varies in nature can have far reaching effects on behavior and metabolism by acting through multiple other genes and pathways.
Author Summary
Normal individual differences in the foraging (for) gene of the fruit fly Drosophila melanogaster result in two behavioral types called rover and sitter. Larval rovers show a greater behavioral response to changes in their food environment than sitters. The for gene makes an enzyme called PKG, which is found in the head of the fly, as well as in most other organisms, including humans. Here, we demonstrate that adult rovers and sitters differ in their metabolic response to changes in their food environment. We measure metabolites in rovers and sitters and show that rovers store energy predominantly as lipids, whereas sitters store it as carbohydrates. We also examine expression levels of genes in rover and sitter heads when the flies are well-fed or food-deprived. We find that for affects levels of gene products involved in carbohydrate and fat metabolism and insulin signaling. We confirm an interaction between for and insulin signaling genes by using genetic mutants to measure their combined effects on fly food-leaving behavior. Our results show that natural variation in this single gene can affect plasticity of large numbers of traits.
PMCID: PMC2720453  PMID: 19696884
6.  Evaluation of a New Rapid Test for the Combined Detection of Hepatitis B Virus Surface Antigen and Hepatitis B Virus e Antigen 
Journal of Clinical Microbiology  2002;40(12):4603-4606.
There are about 350 million chronic hepatitis B virus (HBV) carriers worldwide. A proactive approach to the management of this disease is likely to reduce the morbidity and mortality caused by HBV. This study aimed to evaluate the diagnostic performance of a novel tool for discriminating between infected and noninfected subjects, the hepatitis B sAg/eAg test (Binax Inc., Portland, Maine). The test is designed to rapidly and accurately detect both the HBV surface antigen (HBsAg) and the HBV e antigen (HBeAg). A cohort of 942 subjects was tested. The serum clinical sensitivity of the hepatitis B sAg/eAg test was 99.75 and 96.37% for HBsAg and HBeAg, respectively. Serum clinical specificity was 99.32% for HBsAg and 98.99% for HBeAg. Analytical sensitivity was satisfactory for the purposes of population screening. Visual evaluation showed that the test signals were stable for at least 3 h after the recommended evaluation time. No interference or cross-reactivity was observed with known interfering substances and virologic markers. These results indicate that the hepatitis B sAg/eAg test is well suited to the accurate detection of HBV carriers. In addition to the good clinical specificity and sensitivity of this test, its stability and user-friendly design mean that a correct performance, even under field conditions, is highly likely. Consequently, the hepatitis B sAg/eAg test has the potential to identify subjects who require HBV vaccination (HBsAg− and HBeAg−) and HBV-infected individuals who might benefit most from antiviral therapy (HBsAg+ and HBeAg+).
PMCID: PMC154615  PMID: 12454159
8.  Effects of antituberculosis and antileprosy drugs on mycobacteriophage D29 growth. 
The minimal inhibitory concentrations of antituberculosis and antileprosy drugs were determined for Mycobacterium aurum. The concentrations that reduced the final yield of bacteriophage D29R1 by 50% and the time during the replication cycle at which the drugs completely inhibited phage production were estimated. THe 50% inhibitory concentration/minimal inhibitory concentration ratios were close to 1.0 for clofazimine, colistin, rifampin, and streptomycin; these ratios were high for dapsone (diaminodiphenylsulfone) and isoniazid. Ethambutol (minimal inhibitory concentration, 1.0 micrograms/ml) was without effect on viral growth.
PMCID: PMC283997  PMID: 7447413
9.  Dental legal problems. 
Anesthesia Progress  1969;16(8):230-238.
PMCID: PMC2235597  PMID: 5258938

Results 1-10 (10)