Multiple Environmental Influences Research Articles

An overview of models of stomatal conductance at the leaf level

Stomata play a key role in plant adaptation to changing environmental conditions as they control both water losses and CO(2) uptake. Particularly, in the context of global change, simulations of the consequences of drought on crop plants are needed to design more efficient and water-saving cropping systems. However, most of the models of stomatal conductance (g(s)) developed at the leaf level link g(s) to environmental factors or net photosynthesis (A(net)), but do not include satisfactorily the effects of drought, impairing our capacity to simulate plant functioning in conditions of limited water supply. The objective of this review was to draw an up-to-date picture of the g(s) models, from the empirical to the process-based ones, along with their mechanistic or deterministic bases. It focuses on models capable to account for multiple environmental influences with emphasis on drought conditions. We examine how models that have been proposed for well-watered conditions can be combined with those specifically designed to deal with drought conditions. Ideas for future improvements of g(s) models are discussed: the issue of co-regulation of g(s) and A(net); the roles of CO(2), absissic acid and H(2)O(2); and finally, how to better address the new challenges arising from the issue of global change.

Epigenetic Alterations in Schizophrenia

The inheritance pattern of schizophrenia is complex, with increased rates of illness observed among the first- and second-degree relatives of affected individuals but only about 60% concordance among monozygotic twins. This pattern has been interpreted as indicating that multiple genes and environmental influences may be involved (i.e., “multifactorial” inheritance). Additional epidemiological data, including age of onset in adolescence and young adulthood, varying age of onset between males and females, association between advancing paternal age and risk to offspring, and association with in utero nutritional deficiency, viral exposure, and hypoxia, also suggest that “epigenetic” factors may be important. Epigenetics broadly refers to heritable changes in phenotype or gene expression caused by mechanisms other than changes in the underlying primary DNA sequence. In this review, several major types of epigenetic mechanisms are described, including DNA methylation, genomic imprinting, histone modifications, and expression control by noncoding RNA. Recent data suggesting the influence of these epigenetic alterations in schizophrenia are presented.

Fetal programming: link between early nutrition, DNA methylation, and complex diseases

Complex traits, including those involved in diet-related diseases, are determined by multiple genes and environmental influences. Factors influencing the development of complex traits should be expanded to include epigenetic factors, such as DNA methylation, which occurs in utero. Epigenetic factors regulate gene expression and thereby cell differentiation and organogenesis. The process of epigenotype establishment is sensitive to environmental conditions, with nutrition being one of the most important related factors. For example, DNA methylation depends on the availability of several nutrients including methionine and vitamins B(6), B(12), and folate. Epidemiological studies show that undernutrition during fetal life is associated with increased susceptibility to complex diseases. Numerous studies have been conducted on prenatal caloric and protein undernutrition. A reduction in the number of cells and changes in the structure and functioning of organs, as well as permanent changes in DNA methylation and gene expression, have been considered the molecular mechanisms responsible for metabolism programming.

Genetics Considerations in Cerebral Palsy

Cerebral palsy refers to a collective of neurologic conditions that share in common disorders of motor function and posture. Traditionally, and still today in many circles, the term is considered almost synonymous with brain injury. Multiple lines of evidence, however, point to the fact that cerebral palsy is rarely caused by problems with perinatal management. In fact, a mounting body of evidence points to strong genetic influences on the occurrence of cerebral palsy. Like most neurogenetic conditions, cerebral palsy exhibits complex inheritance. The best descriptor of the inheritance of cerebral palsy would be that of "multifactorial inheritance." This implies etiologic and genetic heterogeneity with complex interactions with multiple environmental influences. This article reviews known genetic influences on the origin of cerebral palsy. A proposed scheme for the genetic evaluation in identifying the etiology of cerebral palsy is provided.

Shared Gene Expression Alterations in Schizophrenia and Bipolar Disorder

Schizophrenia and bipolar disorder together affect approximately 2.5% of the world population, and their etiologies are thought to involve multiple genetic variants and environmental influences. The analysis of gene expression patterns in brain may provide a characteristic signature for each disorder. RNA samples from the dorsolateral prefrontal cortex (Brodmann area 46) consisting of individuals with schizophrenia (SZ), bipolar disorder (BPD), and control subjects were tested on the Codelink Human 20K Bioarray platform. Selected transcripts were validated by quantitative real-time polymerase chain reaction (PCR). The strong effects of age, gender, and pH in the analysis of differential gene expression were controlled by analysis of covariance (ANCOVA). Criteria for differential gene expression were 1) a gene was significantly dysregulated in both BPD and SZ compared with control subjects and 2) significant in ANCOVA analysis with samples that have a pH above the median of the sample. A list of 78 candidate genes passed these two criteria in BPD and SZ and was overrepresented for functional categories of nervous system development, immune system development and response, and cell death. Five dysregulated genes were confirmed with quantitative Q-PCR in both BPD and SZ. Three genes were highly enriched in brain expression (AGXT2L1, SLC1A2, and TU3A). The distribution of AGXT2L1 expression in control subjects versus BPD and SZ was highly significant (Fisher's Exact Test, p < 10(-06)). These results suggest a partially shared molecular profile for both disorders and offer a window into discovery of common pathophysiology that might lead to core treatments.

Social environmental influences on the development and resolution of alcohol problems.

This article summarizes the proceedings of a symposium presented at the 2005 Annual Meeting of the Research Society on Alcoholism, Santa Barbara, California, June 25-30. The overall goal of the symposium was to consider the broad impact of the social environment on the development of and successful or unsuccessful resolution of drinking problems. The presentations addressed multiple social environmental influences including: the influence of children on parents (Dr. Zucker), the influence of peers and parents on adolescents (Dr. Molina), the influence of family members on adult drinking (Dr. McCrady), the influence of adult peers/friends (Dr. Kaskutas), and the influence of the occupational environment (Dr. Ames). Dr. Longabaugh, the symposium discussant, addressed models for understanding the relationships between social influences and drinking problems.

Common variants of multiple genes that control reverse cholesterol transport together explain only a minor part of the variation of HDL cholesterol levels

It is assumed that the combined effects of multiple common genetic variants explain a large part of variation of high-density lipoprotein cholesterol (HDL-C) plasma levels, but little evidence exists to corroborate this assumption. It was our objective to study the contribution of multiple common genetic variants of HDL-C-related genes to variation of HDL-C plasma levels. A well-characterized cohort of 546 Caucasian men with documented coronary artery disease was genotyped for common functional variants in genes that control reverse cholesterol transport: ATP-binding cassette transporter A1, apolipoprotein A-I and apolipoprotein-E, cholesteryl ester transfer protein, hepatic lipase, lecithin : cholesterol-acyl transferase, lipoprotein lipase, and scavenger receptor class B type 1. Multivariate linear regression showed that these variants, in conjunction, explain 12.4% (95% confidence interval: 6.9-17.9%) of variation in HDL-C plasma levels. When the covariates smoking and body mass index were taken into account, the explained variation increased to 15.3% (9.4-21.2%), and when 10 two-way interactions were incorporated, this percentage rose to 25.2% (18.9-31.5%). This study supports the hypothesis that multiple, mildly penetrant, but highly prevalent genetic variants explain part of the variation of HDL-C plasma levels, albeit to a very modest extent. Multiple environmental and genetic influences on HDL-C plasma levels still have to be elucidated.

Pathogenesis of gallstones: a genetic perspective

Cholelithiasis is one of the most prevalent gastroenterological diseases, imposing a huge economic burden on health-care systems. Gallbladder stones form when the concentration of cholesterol or bilirubin exceeds the solubility in the bile salt and phospholipid-rich bile. The physiology of biliary lipid secretion by a number of specialized transport proteins has recently been elucidated, and underlying genetic defects in these proteins have been identified as susceptibility factors for gallstone disease. Recent studies of identical twins and family strongly support the idea of a genetic component to gallstone disease. Epidemiological studies in high-risk populations indicate that gallstone formation is caused by multiple environmental influences and common genetic factors and their interactions. Monogenic subtypes of cholelithiasis, such as biliary lipid transporter deficiencies, appear to be rare. The characterization of lithogenic genes in knockout and transgenic mice, and the identification of many gallstone susceptibility loci in inbred mice, provide the basis for studies of the corresponding genes in patients with gallstones. The transfer of findings from mouse genetics to the bedside might lead to new strategies for individual risk assessment and reveal molecular targets for the development of new treatment strategies.

Mechanisms of Disease: the genetic epidemiology of gallbladder stones

Cholelithiasis is one of the most prevalent and most expensive gastroenterologic diseases. It belongs to the group of complex metabolic disorders that affect humans, and its critical pathogenic mechanisms are not well defined. As a result, primary or secondary prevention strategies are sparse, and the only effective treatment is cholecystectomy. Here we provide an update on the molecular pathogenesis of gallbladder stones, evidence supporting the hypothesis that genetic factors are key elements predisposing to gallstones, and progress in human genetic studies of cholesterol stones. Data from recent identical twin, family and linkage studies provide conclusive evidence for a strong genetic component to gallstone disease. Furthermore, epidemiologic studies in at-risk populations indicate that gallstone formation is caused by multiple environmental influences and common genetic factors and their interactions. By contrast, monogenic subtypes of cholelithiasis, such as ATP-binding-cassette transporter deficiencies, appear to be rare. The summary of human association studies illustrates that distinct common gene variants might contribute to gallstone formation in different ethnic groups. The characterization of lithogenic genes in knockout and transgenic mice and the identification of many gallstone-susceptibility loci in inbred mice provide the basis for studies of the corresponding genes in patients with gallstones. The transfer of findings from mouse genetics to the bedside might lead to new strategies for individual risk assessment and reveal novel molecular targets for prevention and medical therapies.

Theoretical Basis for the Identification of Allelic Variants That Encode Drug Efficacy and Toxicity

Almost all drugs that produce a favorable response (efficacy) may also produce adverse effects (toxicity). The relative strengths of drug efficacy and toxicity that vary in human populations are controlled by the combined influences of multiple genes and environmental influences. Genetic mapping has proven to be a powerful tool for detecting and identifying specific DNA sequence variants on the basis of the haplotype map (HapMap) constructed from single-nucleotide polymorphisms (SNPs). In this article, we present a novel statistical model for sequence mapping of two different but related drug responses. This model is incorporated by mathematical functions of drug response to varying doses or concentrations and the statistical device used to model the correlated structure of the residual (co)variance matrix. We implement a closed-form solution for the EM algorithm to estimate the population genetic parameters of SNPs and the simplex algorithm to estimate the curve parameters describing the pharmacodynamic changes of different genetic variants and matrix-structuring parameters. Extensive simulations are performed to investigate the statistical properties of our model. The implications of our model in pharmacogenetic and pharmacogenomic research are discussed.

Environment and development of atopy

Asthma and other atopic disorders are the result of complex interactions between genetic predisposition and multiple environmental influences. However, the marked increase in asthma prevalence over recent decades is unlikely to be due to genetic changes, highlighting the contribution of environmental factors to the process of allergic sensitization. This article reviews recent information on environmental influences on the development of atopy in children. Both observational and interventional studies continue to shed new light on the critical influence of early life events--such as events in pregnancy, exposure to allergens and endotoxin, pet ownership, infections, family size--and have highlighted important gene-environment interactions that modify the relationships between environmental exposures and atopic outcomes. The future is likely to see a concerted effort to further define the role that these environmental exposures play in allergic sensitization and the expression of atopic diseases, in order to provide a rational platform on which to develop new methods of allergy prevention that can be targeted at high-risk children.

The Nuts and Bolts of an Autoimmune Disorder

Autoimmune disorders, such as systemic lupus erythematosus (SLE), arise from a breakdown of immune tolerance to the body's own constituents and represent the culmination of multiple environmental and genetic influences. Nevertheless, it is likely that specific regulatory pathways of the immune system are perturbed. McGaha et al. studied genetically distinct strains of mice that share a susceptibility to developing SLE and that also express reduced levels of a particular inhibitory antibody-binding receptor. Engineering bone marrow from these animals to express the receptor gene prevented disease by partially restoring levels of the receptor on B cells. Thus, even in the context of multiple contributing factors, the modulation of a single regulatory pathway can be sufficient to dictate the course of autoimmune pathology. T. L. McGaha, B. Sorrentino, J. V. Ravetch, Restoration of tolerance in lupus by targeted inhibitory receptor expression. Science 307 , 590-593 (2005). [Abstract] [Full Text]

An algorithm for molecular dissection of tumor progression

The volumetric growth of tumor cells as a function of time is most often likely to be a complex trait, controlled by the combined influences of multiple genes and environmental influences. Genetic mapping has proven to be a powerful tool for detecting and identifying specific genes affecting complex traits, i.e., quantitative trait loci (QTL), based on polymorphic markers. In this article, we present a novel statistical model for genetic mapping of QTL governing tumor growth trajectories in humans. In principle, this model is a combination of functional mapping proposed to map function-valued traits and linkage disequilibrium mapping designed to provide high resolution mapping of QTL by making use of recombination events created at a historic time. We implement an EM-simplex hybrid algorithm for parameter estimation, in which a closed-form solution for the EM algorithm is derived to estimate the population genetic parameters of QTL including the allele frequencies and the coefficient of linkage disequilibrium, and the simplex algorithm incorporated to estimate the curve parameters describing the dynamic changes of cancer cells for different QTL genotypes. Extensive simulations are performed to investigate the statistical properties of our model. Through a number of hypothesis tests, our model allows for cutting-edge studies aimed to decipher the genetic mechanisms underlying cancer growth, development and differentiation. The implications of our model in gene therapy for cancer research are discussed.

A statistical model for functional mapping of quantitative trait loci regulating drug response.

Differential drug response, that is, pharmacodynamics, is most often likely to be a complex trait, controlled by the combined influences of multiple genes and environmental influences. Genetic mapping has proven to be a powerful tool for detecting and identifying specific genes affecting complex traits, that is, quantitative trait loci (QTL), based on polymorphic markers. In this article, we present a novel statistical model for genetic mapping of QTL governing pharmacodynamic processes. In principle, this model is a combination of functional mapping proposed to map function-valued traits and linkage disequilibrium mapping designed to provide high-resolution mapping of QTL by making use of recombination events created at a historic time. We implement a closed-form solution for the Expectation-Maximization algorithm to estimate the population genetic parameters of QTL and the simplex algorithm to estimate the curve parameters describing the pharmacodynamic changes of different QTL genotypes in response to drug dose or concentrations. Extensive simulations are performed to investigate the statistical properties of our model. The implications of our model in pharmacogenetic and pharmacogenomic research are discussed.

Polymorphism in the transmembrane region of the major histocompatibility complex class I chain-related gene A: association of five GCT repetitions with Graves' disease in children.

Graves' disease is an autoimmune disease involving a complex interplay of multiple genetic and environmental influences. An association between the disorder and the major histocompatibility complex (MHC; human leukocyte antigen [HLA]) region has long been reported. The major histocompatibility complex class I chain-related gene A (MICA) has a triplet repeat polymorphism in the transmembrane region consisting of six alleles. For this study, the polymorphism in question was analyzed for 129 unrelated children with Graves' disease (97 girls and 32 boys, 10.0 +/- 3.0 years of age) and 396 randomly selected, unrelated subjects (205 females, 191 males, 8.4 +/- 13.5 years of age). The frequencies of genotype A5/A5 and A5/A5.1 were significantly higher in patients than in controls (relative risk [RR] = 2.49, 95% confidence interval [CI] 1.52-4.10, p = 0.00024, pc = 0.0035 and RR = 2.13, 95% CI 1.31-3.47, p = 0.0020, pc = 0.030; respectively). The frequency of genotype A5.1/A5.1 was significantly lower in patients than in controls (RR = 0.09, 95% CI 0.01-0.66, p = 0.0030, pc = 0.044). Allele frequency for allele A5 was significantly higher for children with Graves' disease compared to controls (RR = 2.12; 95% CI = 1.59-2.82; p = 1.9 x 10(-7); pc = 9.5 x 10(-7)). This study demonstrates that MICA allele A5 confers the risk for Graves' disease.

Lichenoid Lesion And Oral Squamous Cell Carcinoma Of The Tongue

Supernumerary teeth have a genetic predisposition with a predilection for males. This article reports an uncommon radiological finding in a non-syndromic sibling pair who presented with supernumerary teeth of different morphologies on opposite and different regions of the dental arches. A 14-year-old Chinesemale presented with a conical supernumerary palatally placed between the upper right central and lateral incisors. His older brother had unerupted bilateralsupplemental supernumerary teeth between the roots of the lower second premolars and first permanent molars. Trends of the phenotypic presentation of familial non-syndromic supernumerary cases are discussed. Familial supernumerary teeth have been suggested to be due to autosomal dominance or recessive traits. Variation in the numeral, spatial and morphological phenotypic expressions suggests a multifactorial model of multiple genetic, epigenetic and environmental influences. Clinicians need to be mindful of the possible phenotypic variations that may present when treating cases with family history of dental anomalies.

Using genome-wide mapping in the mouse to identify genes that influence drug response

Differential drug response is most often likely to be a complex trait, controlled by the combined influences of multiple genes and environmental influences. As a result of theoretical and technical limitations, to date, most clinically useful pharmacogenomic studies in humans have been limited to a small number of candidate genes that have a relatively major impact on drug response. Here, the problems involved in identifying genes that underlie drug response in humans are discussed and the power of mouse genetics as a tool for pharmacogenomic discovery is highlighted.

Autoantigenic posttranslational modifications of proteins: does it apply to rheumatoid arthritis?

There are many posttranslational modifications of proteins of which all are homeostatically important either to carry out a particular structural or functional role or to allow efficient recycling of the amino acid constituents. An important feature of the modified proteins is the acquisition of autoantigenicity. That notion should have been recognized for years with the modifications of immunoglobulin G that constitute new targets for rheumatoid factors. Citrullination or the deimination of arginine residues in proteins creates epitopes that are targeted by rheumatoid autoantibodies with a diagnostic sensitivity and specificity of 40% to 70% and 92% to 99%, respectively. The how, when, and why of the responsible break in tolerance are largely speculative but apoptosis, multiple genetic and environmental influences are likely required. Identifying citrullinated proteins as autoantigens has resulted in new diagnostic and prognostic autoantibody markers for RA and studying the citrullination process and its nature and role in cell biology has provided new insights into its pathogenesis.

Association between bone loss in periodontal disease and polymorphism of N-acetyltransferase (NAT2).

The individual susceptibility to periodontal disease is probably the result of an interaction of multiple genetic and environmental influences. Polymorphism of the N-acetyltransferase (NAT 2) modifies the individual susceptibility to toxicity from certain therapeutic drugs or heterocyclic amines including substances from cigarette smoke. Subjects are to be classified as 'slow' or 'rapid' acetylators according to how fast their bodies metabolise such xenobiotics. Differences in their ability to detoxify these substances may contribute to an increased risk for periodontitis in subjects exposed to cigarette smoke or other xenobiotics. The purpose of this study was to assess whether the NAT2 genotype is a risk factor for periodontal disease in Caucasian patients suffering from adult periodontitis. 154 Caucasian subjects were assigned to one of the 3 groups: no, moderate, and severe periodontal disease based on bone and attachment loss. In all subjects, genotyping for mutations on the N-acetyltransferase (NAT2) gene was performed by means of PCR and RFLP analysis. Comparison of frequency distribution of NAT2 acetylation types between the most diseased group and not or moderately affected subjects showed a tendency to over-representation of slow acetylators with severe disease. When using bone loss as measure of periodontitis, this over-representation shows a significant association with the disease (odds ratio=2.13, p=0.025). In the logistic regression analysis, adjusted for age and smoking, NAT2 slow phenotype was significantly associated with the severity of bone loss, the odds ratio being 2.09 (95% C.I. 1.02-4.26, p=0.043). In a case-control analysis (controlled for smoking, gender and age) mean bone loss showed a significant difference between the 2 NAT2-type groups (Mann-Whitney test p=0.041). The data suggest that the slow acetylator phenotype may be associated with a higher risk of periodontitis, especially in smokers. Possible explanations regarding the mechanism are discussed; however, such attempts are highly speculative at this time.

Interlocking patterns of conditional probability: The reinforcement matrix.

Abstract To further integrated behavioral and ecobehavioral models, we introduce the idea of the reinforcement matrix. We define the reinforcement matrix as relatively stable patterns of interlocking contingencies. We can conceptualize this matrix at the ontological level, consisting of varying reinforcement density of dynamic interaction. These interactions occur between interlocking elements of the social and nonsocial environment. Multiple layers of interlocking patterns increase stability and resistance of the ecology to change. These multiple environmental influences act on the organism and lead to gradual shifts in behavior over time. These behavioral shifts are economical in nature based on fluctuations in reinforcement rates, amount of reinforcement, movement toward least effort, and decreasing delay and uncertainty. While relatively stable, the entire process drifts slowly overtime. We identify and discussed factors that lead to this drift. role of metacontingencies, which can lead to rapid shifts or even disturbances in the matrix are discussed. We make suggestions for the study of communities and the development of technology. ********** The experimental analysis of behavior is a rigorous, extensive, and rapidly advancing branch of biology. (Skinner, 1974, p.255) Behavior is the locus of the interaction between organism and environment (Baum, 1994; Hineline, 1992; Skinner, 1981). Through this interaction behavior is selected ontogenetically by environmental consequences (Campbell, 1956; Kimble, 1961; Skinner, 1953, 1981), which correlate with the occurrence of the behavior over time (Baum, 1973). Thus the nature of reinforcement is primarily to serve the organism as a feedback system (Baum, 1973; Hineline & Wanchissen, 1989; Timerlake, 1993, 1995). In this view, variation of behavior is a natural occurrence. Variations that lead to less effort, increased reinforcement density (i.e., higher pay off or higher amount), or decreased aversive stimulation to which the organism is susceptible are selected for continuation in similar contexts (Herrnstein, 1970; Rachlin, Logue, Gibbon, & Frankel, 1986). For theories (Hineline) this process is called adaptation. (4) Variations that correlate with the opposite of the above are selected against recurrence. Also, in novel situations component repertoires can be rapidly integrated in a process called contingency adduction (Andronis, 1983). In this process behavioral classes combine, the product of which then undergoes the selection process (Andronis; Johnson & Layng, 1992; Layng & Andronis, 1984). Moment to moment attempts to maximize the adaptive factors may not lead to maximization over time. We call this process melioration (Herrnstein, 1990). Due to stable environmental elements, relatively stable patterns of interaction form. For example, John Gottman in studying couples discovered that non-distressed couples had a positive to a negative interaction ratio of 5:1 (Gottman, 1993; 1996). In this view we say that the environment-organism-environment system closed-looped (Hineline & Wanchissen, 1989) with contexts of high probability of reinforcement increasing the likelihood of responding (stimulus control). As expected, stimulus control degrades at different rates depending on the species (Balda & Kamil, 1989; Krebs, Healy, & Shettleworth, 1990). Interconnecting patterns of stable probability of reinforcement may lead relatively to stable patterns of interaction over time and even the development of bias (Herrnstein, 1990; McDowell, 1989; Snyder & Patterson, 1995). Bias in responding may develop after prolonged exposure to nonequivalent reinforcer parameters (McDowell; Noll, 1995). This is similar to an idea called homeostasis in organism-based theories. Shifts in stable reinforcement effects can have profound effects not just on the target but on all connected to the pattern. …