Hydroxybenzamide/pyrrole pair distinguishes T·A from A·T base pairs in the minor groove of DNA

A new aromatic pair, 2-hydroxy-6-methoxybenzamide/1-methylpyrrole at the terminal position of hairpin polyamides has been designed for distinguishing T·A from A·T base pairs and both from G·C/C·G in the minor groove of DNA. Four eight-ring hairpin polyamides with benzamide (Bz), 2-hydroxybenzamide (Hb-1), 2-hydroxy-6-methylbenzamide (Hb-2), and 2-hydroxy-6-methoxybenzamide (Hb-3) at the N-terminal position were synthesized. The equilibrium association constants (K_a) were determined at four DNA sites which differ at a single common position, 5‘-TNTACA-3‘ (N = T, A, G, C). Quantitative DNase I footprint titration experiments reveal that (Hb-3)PyPyPy-(R)^H2^Nγ-ImPyPyPy-β-Dp (4) bound the sequences 5‘-TTTACA-3‘ and 5‘-TATACA-3‘ with high affinity; K_a = 2.6 × 10^(10) M^(-1) and K_a = 8.4 × 10^9 M^(-1), respectively, a 3-fold specificity for T vs A was found. Importantly, the sequences 5‘-TGTACA-3‘ and 5‘-TCTACA-3‘ are bound with 50 and 200 times lower affinity, revealing an overall specificity of Hb-3/Py of T > A ≫ G > C. These results expand the repertoire of sequences targetable by hairpin polyamides

Hydroxybenzamide/pyrrole pair distinguishes T·A from A·T base pairs in the minor groove of DNA

A new aromatic pair, 2-hydroxy-6-methoxybenzamide/1-methylpyrrole at the terminal position of hairpin polyamides has been designed for distinguishing T·A from A·T base pairs and both from G·C/C·G in the minor groove of DNA. Four eight-ring hairpin polyamides with benzamide (Bz), 2-hydroxybenzamide (Hb-1), 2-hydroxy-6-methylbenzamide (Hb-2), and 2-hydroxy-6-methoxybenzamide (Hb-3) at the N-terminal position were synthesized. The equilibrium association constants (K_a) were determined at four DNA sites which differ at a single common position, 5‘-TNTACA-3‘ (N = T, A, G, C). Quantitative DNase I footprint titration experiments reveal that (Hb-3)PyPyPy-(R)^H2^Nγ-ImPyPyPy-β-Dp (4) bound the sequences 5‘-TTTACA-3‘ and 5‘-TATACA-3‘ with high affinity; K_a = 2.6 × 10^(10) M^(-1) and K_a = 8.4 × 10^9 M^(-1), respectively, a 3-fold specificity for T vs A was found. Importantly, the sequences 5‘-TGTACA-3‘ and 5‘-TCTACA-3‘ are bound with 50 and 200 times lower affinity, revealing an overall specificity of Hb-3/Py of T > A ≫ G > C. These results expand the repertoire of sequences targetable by hairpin polyamides

Dairy consumption, systolic blood pressure, and risk of hypertension: Mendelian randomization study

Conclusion The weak inverse association between dairy intake and systolic blood pressure in observational studies was not supported by a comprehensive instrumental variable analysis and systematic review of existing clinical trials.</p

The role of thyroid function in borderline personality disorder and schizophrenia: a Mendelian Randomisation study.

BACKGROUND: Genome-wide association studies have reported a genetic overlap between borderline personality disorder (BPD) and schizophrenia (SCZ). Epidemiologically, the direction and causality of the association between thyroid function and risk of BPD and SCZ are unclear. We aim to test whether genetically predicted variations in TSH and FT4 levels or hypothyroidism are associated with the risk of BPD and SCZ. METHODS: We employed Mendelian Randomisation (MR) analyses using genetic instruments associated with TSH and FT4 levels as well as hypothyroidism to examine the effects of genetically predicted thyroid function on BPD and SCZ risk. Bidirectional MR analyses were employed to investigate a potential reverse causal association. RESULTS: Genetically predicted higher FT4 was not associated with the risk of BPD (OR: 1.18; P = 0.60, IVW) or the risk of SCZ (OR: 0.93; P = 0.19, IVW). Genetically predicted higher TSH was not associated with the risk of BPD (OR: 1.11; P = 0.51, IVW) or SCZ (OR: 0.98, P = 0.55, IVW). Genetically predicted hypothyroidism was not associated with BPD or SCZ. We found no evidence for a reverse causal effect between BPD or SCZ on thyroid function. CONCLUSIONS: We report evidence for a null association between genetically predicted FT4, TSH or hypothyroidism with BPD or SCZ risk. There was no evidence for reverse causality

Hereditary Hemochromatosis (HFE) genotypes in heart failure: Relation to etiology and prognosis

<p>Abstract</p> <p>Background</p> <p>It is believed that hereditary hemochromatosis (HH) might play a role in cardiac disease (heart failure (HF) and ischemia). Mutations within several genes are HH-associated, the most common being the <it>HFE </it>gene. In a large cohort of HF patients, we sought to determine the etiological role and the prognostic significance of <it>HFE </it>genotypes.</p> <p>Methods</p> <p>We studied 667 HF patients (72.7% men) with depressed systolic function, enrolled in a multicentre trial with a follow-up period of up to 5 years. All were genotyped for the known <it>HFE </it>variants C282Y, H63D and S65C.</p> <p>Results</p> <p>The genotype and allele frequencies in the HF group were similar to the frequencies determined in the general Danish population. In multivariable analysis mortality was not predicted by C282Y-carrier status (HR 1.2, 95% CI: 0.8-1.7); H63D-carrier status (HR 1.0, 95% CI: 0.7-1.3); nor S65C-carrier status (HR 1.2, 95% CI: 0.7-2.0). We identified 27 (4.1%) homozygous or compound heterozygous carriers of <it>HFE </it>variants. None of these carriers had a clinical presentation suggesting hemochromatosis, but hemoglobin and ferritin levels were higher than in the rest of the cohort. Furthermore, a trend towards reduced mortality was seen in this group in univariate analyses (HR 0.4, 95% CI: 0.2-0.9, p = 0.03), but not in multivariate (HR 0.5, 95% CI: 0.2-1.2).</p> <p>Conclusion</p> <p><it>HFE </it>genotypes do not seem to be a significant contributor to the etiology of heart failure in Denmark. <it>HFE </it>variants do not affect mortality in HF.</p