RNA secondary structure formation: a solvable model of heteropolymer folding

The statistical mechanics of heteropolymer structure formation is studied in the context of RNA secondary structures. A designed RNA sequence biased energetically towards a particular native structure (a hairpin) is used to study the transition between the native and molten phase of the RNA as a function of temperature. The transition is driven by a competition between the energy gained from the polymer's overlap with the native structure and the entropic gain of forming random contacts. A simplified Go-like model is proposed and solved exactly. The predicted critical behavior is verified via exact numerical enumeration of a large ensemble of similarly designed sequences.Comment: 4 pages including 2 figure

Prenatal exposure to organophosphates, paraoxonase 1, and cognitive development in childhood

Background: Prenatal exposure to organophosphate pesticides has been shown to negatively affect child neurobehavioral development. Paraoxonase 1 (PON1) is a key enzyme in the metabolism of organophosphates. Objective: We examined the relationship between biomarkers of organophosphate exposure, PON1, and cognitive development at ages 12 and 24 months and 6-9 years. Methods: The Mount Sinai Children's Environmental Health Study enrolled a multiethnic prenatal population in New York City between 1998 and 2002 (n = 404). Third-trimester maternal urine samples were collected and analyzed for organophosphate metabolites (n = 360). Prenatal maternal blood was analyzed for PON1 activity and genotype. Children returned for neurodevelopment assessments ages 12 months (n = 200), 24 months (n = 276), and 6-9 (n = 169) years of age. Results: Prenatal total dialkylphosphate metabolite level was associated with a decrement in mental development at 12 months among blacks and Hispanics. These associations appeared to be enhanced among children of mothers who carried the PON1 Q192R QR/RR genotype. In later childhood, increasing prenatal total dialkyl- and dimethylphosphate metabolites were associated with decrements in perceptual reasoning in the maternal PON1 Q192R QQ genotype, which imparts slow catalytic activity for chlorpyrifos oxon, with a monotonic trend consistent with greater decrements with increasing prenatal exposure. Conclusion: Our findings suggest that prenatal exposure to organophosphates is negatively associated with cognitive development, particularly perceptual reasoning, with evidence of effects beginning at 12 months and continuing through early childhood. PON1 may be an important susceptibility factor for these deleterious effects

Enhanced annealing of mismatched oligonucleotides using a novel melting curve assay allows efficient in vitro discrimination and restriction of a single nucleotide polymorphism

<p>Abstract</p> <p>Background</p> <p>Many SNP discrimination strategies employ natural restriction endonucleases to discriminate between allelic states. However, SNPs are often not associated with a restriction site and therefore, a number of attempts have been made to generate sequence-adaptable restriction endonucleases. In this study, a simple, sequence-adaptable SNP discrimination mechanism between a 'wild-type' and 'mutant' template is demonstrated. This model differs from other artificial restriction endonuclease models as <it>cis- </it>rather than <it>trans-</it>orientated regions of single stranded DNA were generated and cleaved, and therefore, overcomes potential issues of either inefficient or non-specific binding when only a single variant is targeted.</p> <p>Results</p> <p>A series of mismatch 'bubbles' that spanned 0-5-bp surrounding a point mutation was generated and analysed for sensitivity to S1 nuclease. In this model, generation of oligonucleotide-mediated ssDNA mismatch 'bubbles' in the presence of S1 nuclease resulted in the selective degradation of the mutant template while maintaining wild-type template integrity. Increasing the size of the mismatch increased the rate of mutant sequence degradation, until a threshold above which discrimination was lost and the wild-type sequence was degraded. This level of fine discrimination was possible due to the development of a novel high-resolution melting curve assay to empirically determine changes in Tm (~5.0°C per base-pair mismatch) and to optimise annealing conditions (~18.38°C below Tm) of the mismatched oligonucleotide sets.</p> <p>Conclusions</p> <p>The <it>in vitro </it>'cleavage bubble' model presented is sequence-adaptable as determined by the binding oligonucleotide, and hence, has the potential to be tailored to discriminate between any two or more SNPs. Furthermore, the demonstrated fluorometric assay has broad application potential, offering a rapid, sensitive and high-throughput means to determine Tm and annealing rates as an alternative to conventional hybridisation detection strategies.</p

Lead and δ-Aminolevulinic Acid Dehydratase Polymorphism: Where Does It Lead? A Meta-Analysis

BACKGROUND: Lead poisoning affects many organs in the body. Lead inhibits δ-aminolevulinic acid dehydratase (ALAD), an enzyme with two co-dominantly expressed alleles, ALAD1 and ALAD2. OBJECTIVE: Our meta-analysis studied the effects of the ALAD polymorphism on a) blood and bone lead levels and b) indicators of target organ toxicity. DATA SOURCE: We included studies reporting one or more of the following by individuals with genotypes ALAD1-1 and ALAD1-2/2-2: blood lead level (BLL), tibia or trabecular lead level, zinc protoporphyrin (ZPP), hemoglobin, serum creatinine, blood urea nitrogen (BUN), dimercaptosuccinic acid–chelatable lead, or blood pressure. DATA EXTRACTION: Sample sizes, means, and standard deviations were extracted for the genotype groups. DATA SYNTHESIS: There was a statistically significant association between ALAD2 carriers and higher BLL in lead-exposed workers (weighted mean differences of 1.93 μg/dL). There was no association with ALAD carrier status among environmentally exposed adults with BLLs < 10 μg/dL. ALAD2 carriers were potentially protected against adverse hemapoietic effects (ZPP and hemoglobin levels), perhaps because of decreased lead bioavailability to heme pathway enzymes. CONCLUSION: Carriers of the ALAD2 allele had higher BLLs than those who were ALAD1 homozygous and higher hemoglobin and lower ZPP, and the latter seems to be inversely related to BLL. Effects on other organs were not well delineated, partly because of the small number of subjects studied and potential modifications caused by other proteins in target tissues or by other polymorphic genes

High intakes of choline and betaine reduce breast cancer mortality in a population-based study

Choline and betaine provide methyl groups for one-carbon metabolism. Humans obtain these nutrients from a wide range of foods. Betaine can also be synthesized endogenously from its precursor, choline. Although animal studies have implied a causal relationship between choline deficiency and carcinogenesis, the role of these two nutrients in human carcinogenesis and tumor progression is not well understood. We investigated the associations of dietary intakes of choline and betaine and breast cancer risk and mortality in the population-based Long Island Breast Cancer Study Project. Among the 1508 case-group women, 308 (20.2%) deaths occurred, among whom 164 (53.2%) died of breast cancer by December 31, 2005. There was an indication that a higher intake of free choline was associated with reduced risk of breast cancer (P trend=0.04). Higher intakes of betaine, phosphocholine, and free choline were associated with reduced all-cause as well as breast cancerspecific mortality in a dose-dependent fashion. We also explored associations of polymorphisms of three key choline- and betaine-metabolizing genes and breast cancer mortality. The betaine-homocysteine methyltransferase gene (BHMT) rs3733890 polymorphism was associated with reduced breast cancer-specific mortality (hazard ratio, 0.64; 95% confidence interval, 0.42-0.97). Our study supports the important roles of choline and betaine in breast carcinogenesis. It suggests that high intake of these nutrients may be a promising strategy to prevent the development of breast cancer and to reduce its mortality

Prenatal exposure to organophosphorus pesticides and childhood neurodevelopmental phenotypes

Prenatal exposure to organophosphorus pesticides (OPs) has been associated with different neurodevelopmental outcomes across different cohorts. A phenotypic approach may address some of these differences by incorporating information across scales and accounting for the complex correlational structure of neurodevelopmental outcomes. Additionally, Bayesian hierarchical modeling can account for confounding by collinear co-exposures. We use this framework to examine associations between prenatal exposure to OPs and behavior, executive functioning, and IQ assessed at age 6–9 years in a cohort of 404 mother/infant pairs recruited during pregnancy. We derived phenotypes of neurodevelopment with a factor analysis, and estimated associations between OP metabolites and these phenotypes in Bayesian hierarchical models for exposure mixtures. We report seven factors: 1) Impulsivity and Externalizing, 2) Executive Functioning, 3) Internalizing, 4) Perceptual Reasoning, 5) Adaptability, 6) Processing Speed, and 7) Verbal Intelligence. These, along with the Working Memory Index, were standardized and scaled so that positive values reflected positive attributes and negative values represented adverse outcomes. Standardized dimethylphosphate metabolites were negatively associated with Internalizing factor scores (β^ − 0.13, 95% CI − 0.26, 0.00) but positively associated with Executive Functioning factor scores (β^ 0.18, 95% CI 0.04, 0.31). Standardized diethylphosphate metabolites were negatively associated with the Working Memory Index (β^ − 0.17, 95% CI − 0.33, − 0.03). Associations with factor scores were generally stronger and more precise than associations with individual instrument-specific items. Factor analysis of outcomes may provide some advantages in etiological studies of childhood neurodevelopment by incorporating information across scales to reduce dimensionality and improve precision

Comprehensive Analysis of 5-Aminolevulinic Acid Dehydrogenase (ALAD) Variants and Renal Cell Carcinoma Risk among Individuals Exposed to Lead

BACKGROUND: Epidemiologic studies are reporting associations between lead exposure and human cancers. A polymorphism in the 5-aminolevulinic acid dehydratase (ALAD) gene affects lead toxicokinetics and may modify the adverse effects of lead. METHODS: The objective of this study was to evaluate single-nucleotide polymorphisms (SNPs) tagging the ALAD region among renal cancer cases and controls to determine whether genetic variation alters the relationship between lead and renal cancer. Occupational exposure to lead and risk of cancer was examined in a case-control study of renal cell carcinoma (RCC). Comprehensive analysis of variation across the ALAD gene was assessed using a tagging SNP approach among 987 cases and 1298 controls. Occupational lead exposure was estimated using questionnaire-based exposure assessment and expert review. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression. RESULTS: The adjusted risk associated with the ALAD variant rs8177796(CT/TT) was increased (OR = 1.35, 95%CI = 1.05-1.73, p-value = 0.02) when compared to the major allele, regardless of lead exposure. Joint effects of lead and ALAD rs2761016 suggest an increased RCC risk for the homozygous wild-type and heterozygous alleles ((GG)OR = 2.68, 95%CI = 1.17-6.12, p = 0.01; (GA)OR = 1.79, 95%CI = 1.06-3.04 with an interaction approaching significance (p(int) = 0.06). No significant modification in RCC risk was observed for the functional variant rs1800435(K68N). Haplotype analysis identified a region associated with risk supporting tagging SNP results. CONCLUSION: A common genetic variation in ALAD may alter the risk of RCC overall, and among individuals occupationally exposed to lead. Further work in larger exposed populations is warranted to determine if ALAD modifies RCC risk associated with lead exposure

Immunolocalization of Influenza A Virus and Markers of Inflammation in the Human Parkinson's Disease Brain

Although much is known regarding the molecular mechanisms leading to neuronal cell loss in Parkinson's disease (PD), the initiating event has not been identified. Prevailing theories including a chemical insult or infectious agent have been postulated as possible triggers, leading to neuroinflammation. We present immunohistochemical data indicating the presence of influenza A virus within the substantia nigra pars compacta (SNpc) from postmortem PD brain sections. Influenza A virus labeling was identified within neuromelanin granules as well as on tissue macrophages in the SNpc. Further supporting a role for neuroinflammation in PD was the identification of T-lymphocytes that colocalized with an antibody to caspase-cleaved Beclin-1 within the SNpc. The presence of influenza A virus together with macrophages and T-lymphocytes may contribute to the neuroinflammation associated with this disease