Transient amplifiers of selection and reducers of fixation for death-Birth updating on graphs.

The spatial structure of an evolving population affects the balance of natural selection versus genetic drift. Some structures amplify selection, increasing the role that fitness differences play in determining which mutations become fixed. Other structures suppress selection, reducing the effect of fitness differences and increasing the role of random chance. This phenomenon can be modeled by representing spatial structure as a graph, with individuals occupying vertices. Births and deaths occur stochastically, according to a specified update rule. We study death-Birth updating: An individual is chosen to die and then its neighbors compete to reproduce into the vacant spot. Previous numerical experiments suggested that amplifiers of selection for this process are either rare or nonexistent. We introduce a perturbative method for this problem for weak selection regime, meaning that mutations have small fitness effects. We show that fixation probability under weak selection can be calculated in terms of the coalescence times of random walks. This result leads naturally to a new definition of effective population size. Using this and other methods, we uncover the first known examples of transient amplifiers of selection (graphs that amplify selection for a particular range of fitness values) for the death-Birth process. We also exhibit new families of "reducers of fixation", which decrease the fixation probability of all mutations, whether beneficial or deleterious.

Quantifying the Contribution of Habitats and Pathways to a Spatially Structured Population Facing Environmental Change.

The consequences of environmental disturbance and management are difficult to quantify for spatially structured populations because changes in one location carry through to other areas as a result of species movement. We develop a metric, G, for measuring the contribution of a habitat or pathway to network-wide population growth rate in the face of environmental change. This metric is different from other contribution metrics, as it quantifies effects of modifying vital rates for habitats and pathways in perturbation experiments. Perturbation treatments may range from small degradation or enhancement to complete habitat or pathway removal. We demonstrate the metric using a simple metapopulation example and a case study of eastern monarch butterflies. For the monarch case study, the magnitude of environmental change influences the ordering of node contribution. We find that habitats within which all individuals reside during one season are the most important to short-term network growth under complete removal scenarios, whereas the central breeding region contributes most to population growth over all but the strongest disturbances. The metric G provides for more efficient management interventions that proactively mitigate impacts of expected disturbances to spatially structured populations.

The molecular clock of neutral evolution can be accelerated or slowed by asymmetric spatial structure.

Over time, a population acquires neutral genetic substitutions as a consequence of random drift. A famous result in population genetics asserts that the rate, K, at which these substitutions accumulate in the population coincides with the mutation rate, u, at which they arise in individuals: K = u. This identity enables genetic sequence data to be used as a "molecular clock" to estimate the timing of evolutionary events. While the molecular clock is known to be perturbed by selection, it is thought that K = u holds very generally for neutral evolution. Here we show that asymmetric spatial population structure can alter the molecular clock rate for neutral mutations, leading to either Ku. Our results apply to a general class of haploid, asexually reproducing, spatially structured populations. Deviations from K = u occur because mutations arise unequally at different sites and have different probabilities of fixation depending on where they arise. If birth rates are uniform across sites, then K ≤ u. In general, K can take any value between 0 and Nu. Our model can be applied to a variety of population structures. In one example, we investigate the accumulation of genetic mutations in the small intestine. In another application, we analyze over 900 Twitter networks to study the effect of network topology on the fixation of neutral innovations in social evolution.

Nonlinear social evolution and the emergence of collective action.

Organisms from microbes to humans engage in a variety of social behaviors, which affect fitness in complex, often nonlinear ways. The question of how these behaviors evolve has consequences ranging from antibiotic resistance to human origins. However, evolution with nonlinear social interactions is challenging to model mathematically, especially in combination with spatial, group, and/or kin assortment. We derive a mathematical condition for natural selection with synergistic interactions among any number of individuals. This result applies to populations with arbitrary (but fixed) spatial or network structure, group subdivision, and/or mating patterns. In this condition, nonlinear fitness effects are ascribed to collectives, and weighted by a new measure of collective relatedness. For weak selection, this condition can be systematically evaluated by computing branch lengths of ancestral trees. We apply this condition to pairwise games between diploid relatives, and to dilemmas of collective help or harm among siblings and on spatial networks. Our work provides a rigorous basis for extending the notion of "actor", in the study of social evolution, from individuals to collectives.

Identification of genes contributing to cardiovascular disease in overweight and obese individuals from West Virginia.

Excess weight is a known risk factor for coronary artery disease (CAD) and a large percentage of overweight and obese individuals ultimately develop CAD. The objective of this study was to identify human genes associated with CAD in a subgroup of overweight and obese individuals using population-based association methods. Logistic regression analyses were used to test the association between single nucleotide polymorphisms (SNPs) in 34 candidate genes and the CAD phenotype with age, gender, and BMI as covariates. Two SNPs in the Apolipoprotein B (Apo B) gene [rs1042031 and rs1800479], one in the Cholesterol Ester Transfer Protein (CETP) gene [rs5880], and one in the Low Density Lipoprotein Receptor (LDLR) gene [rs2569538] met the 0.01 significance level for association with CAD. Based on these findings, we conclude that variants within the CETP and Apo B genes conferred susceptibility to CAD in overweight individuals and that a variant with the LDLR gene conferred susceptibility in an obese group.

Eradication of therapy-resistant human prostate tumors using an ultrasound-guided site-specific cancer terminator virus delivery approach.

Intratumoral injections of a replication-incompetent adenovirus (Ad) expressing melanoma differentiation-associated gene-7/interleukin-24 (Ad.mda-7), a secreted cytokine displaying cancer-selective, apoptosis-inducing properties, profoundly inhibits prostate cancer (PC) growth in immune-incompetent animals. In contrast, Ad.mda-7 is ineffective in PCs overexpressing antiapoptotic proteins such as Bcl-2 or Bcl-x(L). However, intratumoral injections of a conditionally replication-competent Ad (CRCA) in which expression of the adenoviral E1A gene is driven by the cancer-specific promoter of progression-elevated gene-3 (PEG-3) and which simultaneously expresses mda-7/interleukin (IL)-24 in the E3 region of the Ad (Ad.PEG-E1A-mda-7), a cancer terminator virus (CTV), is highly active in these cells. A major challenge for gene therapy is systemic delivery of nucleic acids directly into an affected tissue. Ultrasound (US) contrast agents (microbubbles-MBs) are viable candidates for gene delivery/therapy. Here, we show that MB/Ad.mda-7 complexes targeted to DU-145 cells using US dramatically reduced tumor burden in xenografted nude mice. Additionally, US-guided MB/CTV delivery completely eradicated not only targeted DU-145/Bcl-x(L)-therapy-resistant tumors, but also nontargeted distant tumors (established in the opposite flank), thereby implementing a cure. These findings highlight potential therapeutic applications of this novel image-guided gene therapy technology for advanced PC patients with metastatic disease.

Helicobacter pylori infection rate decreases in symptomatic children: a retrospective analysis of 13 years (1993-2005) from a gastroenterology clinic in West Virginia.

BACKGROUND: The rate of Helicobacter pylori is decreasing in the developed countries, but few long-term studies are available from the United States. We retrospectively assessed the annual H. pylori infection rate in symptomatic children seen in our clinic over a 13-year study period. STUDY: A retrospective analysis of all children who had histologic diagnosis of H. pylori infection between January 1993 and December 2005 in our pediatric gastroenterology clinic was performed. The annual infection rate and the overall infection rate were calculated. RESULTS: A total of 1743 upper endoscopy reports were reviewed, of which 212 (12.1%) were diagnosed with H. pylori infection. A significant decrease in mean annual H. pylori infection rate was noted in the last 6 years of the study period (2000 to 2005), compared with the first 7 years (1993 to 1999) (18.2% vs. 7.3%, respectively; P=0.001). CONCLUSIONS: The incidence of H. pylori infection in symptomatic children in our clinic is decreasing. A national multicenter study will be needed to assess whether this drop is a local phenomenon or a national trend.

Accelerated head growth in early development of individuals with autism.

Macrocephaly is one of the most consistent physical findings reported in autistic individuals. Previous studies attempted to determine if macrocephaly is associated with risk for autism. This study hypothesizes that an abnormal acceleration in head growth during early development, rather than macrocephaly, is associated with autism risk. To investigate this hypothesis, head circumference data were examined in 251 individuals from 82 multiplex (at least two individuals with autism) and 113 sporadic (no family history) families with autism. This examination included longitudinal measurements for 79 individuals. Nineteen percent of the original 251 individuals were found to have macrocephaly (head circumference >97%). Abnormal acceleration in head growth was defined as an increase of 25 or more percentile points in head circumference between two consecutive measurements. Thirty-five percent of individuals with multiple head circumference records had an abnormal increase in head circumference. Furthermore, autistic individuals with accelerated head growth in early childhood displayed higher levels of adaptive functioning and less social impairment. This study confirms the presence of abnormal acceleration in head growth during the first and second months of life in a subgroup of autistic individuals.

Analysis of European mitochondrial haplogroups with Alzheimer disease risk.

We examined the association of mtDNA variation with Alzheimer disease (AD) risk in Caucasians (989 cases and 328 controls) testing the effect of individual haplogroups and single nucleotide polymorphisms (SNPs). Logistic regression analyses were used to assess risk of haplogroups and SNPs with AD in both main effects and interaction models. Males classified as haplogroup U showed an increase in risk (OR = 2.30; 95% CI, 1.03-5.11; P = 0.04) of AD relative to the most common haplogroup H, while females demonstrated a significant decrease in risk with haplogroup U (OR = 0.44 ; 95% CI, 0.24-0.80; P = 0.007). Our results were independent of APOE genotype, demonstrating that the effect of mt variation is not confounded by APOE4 carrier status. We suggest that variations within haplogroup U may be involved in AD expression in combination with environmental exposures or nuclear proteins other than APOE.

Fatal methadone toxicity: potential role of CYP3A4 genetic polymorphism.

Methadone is difficult to administer as a therapeutic agent because of a wide range of interindividual pharmacokinetics, likely due to genetic variability of the CYP450 enzymes responsible for metabolism to its principal metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP). CYP3A4 is one of the primary CYP450 isoforms responsible for the metabolism of methadone to EDDP in humans. The purpose of this study was to evaluate the role of CYP3A4 genetic polymorphisms in accidental methadone fatalities. A study cohort consisting of 136 methadone-only and 92 combined methadone/benzodiazepine fatalities was selected from cases investigated at the West Virginia and Kentucky Offices of the Chief Medical Examiner. Seven single nucleotide polymorphisms (SNPs) were genotyped within the CYP3A4 gene. Observed allelic and genotypic frequencies were compared with expected frequencies obtained from The National Center for Biotechnology Information dbSNP database. SNPs rs2242480 and rs2740574 demonstrated an apparent enrichment within the methadone-only overdose fatalities compared with the control group and the general population. This enrichment was not apparent in the methadone/benzodiazepine cases for these two SNPs. Our findings indicate that there may be two or more SNPs on the CYP3A4 gene that cause or contribute to the methadone poor metabolizer phenotype.

Why Has the BMI gone up so drastically in the last 35 years?

OBJECTIVES: We attempted to answer the following questions: Why has the body mass index (BMI) increased so dramatically in the last 35 years? Are some food groups or additives more responsible than others? METHODS: Data for per capita food production available for consumption after spoilage for different food groups and additives from the US Department of Agriculture were used as independent variables to predict BMI increases. The heights and weights were taken from the Centers for Disease Control and the US Census Bureau for the years 1970 to 2004. RESULTS: The additives of fats and sugars in combination, not separately, best predicted increases in BMI accounting for 97% of the variance in the linear regression analyses. When all food groups were entered into regressions to predict increases in BMI, fats and sugars in combination accounted for 96% of the variance for women and 97% for men, with the other food groups adding very little. Path analyses showed that fat and sweeteners had direct effects on BMI and were also the mediators of increased caloric consumption. CONCLUSIONS: In line with the major physiological theories emphasizing palatability as the addictive stimulus in models of incentives and addiction, fats and sugars in combination rather than calories per se or particular food groups accounted for the increases in BMI. These empirically based theories and data suggest that one should focus on palatability and addictive models in dealing with the increasing problem of obesity in the United States.

Acanthosis nigricans as a clinical marker to detect insulin resistance in Caucasian children from West Virginia.

The accuracy of acanthosis nigrcans (AN) as a dermatological clinical marker to predict insulin resistance (IR) has not been well established in children. A cohort of obese Caucasian children was prospectively recruited. Demographic data, body mass index values, and laboratory data were compared for the presence or absence of AN. A total of 76 children participated. In all, 46 (60.5%) children had AN, and 34 (44.7%) children were positive for IR (>3.16); 25 (32.9%) children were positive for both AN and IR. Sensitivity, specificity, positive and negative predictive values, and accuracy level for AN to detect IR in the obese children who participated in this study were 73.5%, 50%, 54.3%, 70%, and 49%, respectively. The correlation between insulin and fasting glucose levels in AN-negative or AN-positive patients was low (R (2) = 13% to 17%). Acanthosis nigricans was only a surrogate marker for IR. It is concluded that IR should be examined in every obese West Virginian child irrespective of his or her AN status.

A high omega-3 fatty acid diet has different effects on early and late stage myeloid progenitors.

The effects of the polyunsaturated omega-3 (n-3) and omega-6 (n-6) fatty acids (FA) on hematopoiesis are complex in that both FA forms are processed into leukotrienes, eicosanoids, and prostaglandins, which can have independent effects. These FA have antagonistic effects in that n-6 FA prostaglandins tend to be pro-proliferative and pro-inflammatory, while the effects of n-3 FA prostaglandins are the opposite. We have previously shown that diets high in n-3 FA reduce the size of the middle to later stage myeloid progenitor compartment in FVB X sv129 F(1)hybrid mice. To assay the effects of high n-3 FA diets on earlier stages of myelopoiesis, we fed C57BL/6J mice diets high in n-3 FA or levels of n-3/n-6 FA similar to western diets and assayed the effects on myelopoiesis with flow cytometry and colony forming cell assays. Results indicate an expansion of the common myeloid progenitor cell compartment in high n-3 FA diets, which does not persist into later stages where the number of progenitor cells is actually lower in high n-3 FA fed animals. Investigations in vitro with the hematopoietic stem cell line EML-clone 1 indicate that cells cultured with eicosapentaenoic acid (n-3 FA) or arachidonic acid (n-6 FA) have no differences in cell viability but that arachidonic acid more rapidly produces progenitors with low levels of the macrophage developmental marker, F4/80.

Identification of the early VIP-regulated transcriptome and its associated, interactome in resting and activated murine CD4 T cells.

More than 40 years after the discovery of vasoactive intestinal peptide (VIP), its transcriptome in the immune system has still not been completely elucidated. In an attempt to understand the biological role of this neuropeptide in immunity, we chose CD4 T cells as a cellular system. Agilent Mouse Whole Genome microarrays were hybridized with fluorescently labeled total RNA isolated from resting CD4 T cells cultured +/-10(-7)M VIP for 5h or PMA/ionomycin activated CD4 T cells cultured +/-10(-7)M VIP for 5h. These VIP-regulated transcriptomes were analyzed by Significance Analysis of Microarrays (SAM) and Ingenuity Pathway Analysis (IPA) software to identify relevant signaling pathways modulated by VIP in the absence and presence of T cell activation. In resting CD4 T cells, VIP-modulated 368 genes, ranging from 3.49 to -4.78-fold. In the PMA/ionomycin activated CD4 T cells, 326 gene expression levels were changed by VIP, ranging from 2.94 to -1.66-fold. IPA analysis revealed that VIP exposure alters cellular function through EGFR signaling in resting CD4 T cells, and modulates immediate early genes, Fos and CREM/ICER, in activated CD4 T cells. These gene expression changes are suggested to explain at a molecular level how VIP can regulate T cell homing to the gut and induce regulatory T cell generation.

Obesity is not a risk factor in children with reflux esophagitis: a retrospective analysis of 738 children.

Obesity has been associated with various gastrointestinal diseases in children, but the role of obesity in gastroesophageal reflux disease (GERD) has not been clearly established. The aim of the study was to investigate whether obesity and/or being overweight are risk factors for reflux esophagitis in children. A retrospective analysis of endoscopy charts was reviewed. Demographic, weight, height, and histology results were obtained from each patient. The body mass index (BMI) and BMI Z-score were calculated according to known formula. The diagnosis of GERD was established by histology. The charts of 738 children were reviewed; of these, 345 (47%) children were overweight or obese. Histological findings compatible with GERD were found in 254 (65%) children with normal weight, 111 (69%) overweight children, and 126 (68%) obese children (P > 0.05). Among those reviewed, the mean age of children with normal weight was significantly younger than that of overweight or obese children (P = 0.0001). A single variant analysis showed a significant association between GERD and male gender (P = 0.0001). Multivariant analysis (gender, age, and BMI Z-score) showed that GERD was significantly associated with male gender (P < 0.0001), but not with age (P = 0.443) or BMI Z-score (P = 0.098). In symptomatic children with histologically proven GERD, only male gender was an independent risk factor for GERD, not obesity or being overweight. Large, prospective studies in children that capture a larger spectrum of GERD are clearly warranted.

Proteomic and genomic analysis of PITX2 interacting and regulating networks.

Pituitary homeobox 2 (PITX2) is a homeodomain transcription factor that has a substantial role in cell proliferation and differentiation in various tissues. In this report, we have conducted a systematic study, using proteomic and genomic approaches, to characterize PITX2-interacting proteins and PITX2-regulating genes. We identified four novel PITX2-associated protein partners Y box binding factor-1, heterogeneous ribonucleoprotein K, nucleolin and heterogeneous nuclear ribonucleoprotein U in mass spectrometry analysis. We also found that overexpression of PITX2 upregulated 868 genes (2-25-fold) and downregulated 191 genes (2-15-fold) in DNA microarray analysis. These data provide an insightful perspective for further studying PITX2 function and mechanism of action.