Cluster DNA damage refers to two or more lesions in a single turn of the DNA helix. Such clustering may occur with bulky DNA lesions, which may be responsible for their sequence-dependent repair and mutational outcomes. Here we prepared three 16-mer cluster duplexes in which two fluoroacetylaminofluorene adducts (dG-FAAF) are separated by zero, one, and two nucleotides in the Escherichia coli NarI mutational hot spot (5′-CTCTCG1G 2CG3CCATCAC-3′): 5′-CG1* G2*CG3CC-3′, 5′-CG1G 2*CG3*CC-3′, and 5′-CG 1*G2CG3*CC-3′ (G* = dG-FAAF), respectively. We conducted spectroscopic, thermodynamic, and molecular dynamics studies of these di-FAAF duplexes, and the results were compared with those of the corresponding mono-FAAF adducts in the same NarI sequence [Jain, V., et al. (2012) Nucleic Acids Res. 40, 3939-3951]. Our nucleotide excision repair results showed the diadducts were more reparable than the corresponding monoadducts. Moreover, we observed dramatic flanking base sequence effects on their repair efficiency in the following order: NarI-G2G3 > NarI-G1G3 > NarI-G1G2. The nuclear magnetic resonance, circular dichroism, ultraviolet melting, and molecular dynamics simulation results revealed that in contrast to the monoadducts, diadducts produced a synergistic effect on duplex destabilization. In addition, dG-FAAF at G2G3 and G1G 3 destacks the neighboring bases, with greater destabilization occurring with the former. Overall, the results indicate the importance of base stacking and related thermal and thermodynamic destabilization in the repair of bulky cluster arylamine DNA adducts.

The influence of stress agents, whether social, restraint, malnutrition or mild unpredictable, during the fetal-prenatal, infant-postnatal, adolescent or young adult phases of the lifespan generally, but not always, implies disruption of the normal process of development. Several notions of stress including the adaptive calibration model, adaptive emotional processes and arousability, GABAergic integrity and nutrient deficiency, and resilience influence the physiological and behavioural expressions of maternal stress, affecting nursing behaviour and offspring outcome. The adaptive/maladaptive effects of stress in humans are affected by developmental programming of the hypothalamic-pituitary-adrenal (HPA) axis and other neuroendocrine systems related to stress that may facilitate expressions of resilience. The adaptive/maladaptive effects of stress in animal models outline dysfunctional HPA axis and brain regional alterations of phenotypic expressions that interact with epigenetic mechanisms and developmental plasticity. Maladaptive stress regulation in adolescence is influenced by several factors, not the least being serotonergic, glucocorticoid and regional integrity pertaining to trauma in adolescence. The occurrence of oxidative stress may imply damage but the propensity for hormesis, a notion not unrelated to resilience, provides opportunities for long-lasting health benefits.

Recent multichannel electrode array technology has enabled the simultaneous recording of multiple cardiac neurons located in ganglia on a beating heart. These new bioelectric signals are contaminated by the electrical activity of the atrial muscle just underneath. These atrial waveforms may mask relevant neuronal activity. In this paper, we evaluate the application of a principal component analysis technique to suppress atrial activity (AA) and reveal hidden neuronal activity. Neuronal signals were recorded in situ using a 16-channel electrode in an open-chest, anesthetized dog in sinus rhythm. Validation of AA cancellation was performed by comparing neuron spike waveforms extracted from within AA with those found in AA-free time intervals. Results showed that consistent neuronal waveforms can be identified within AA in order to improve the detection of neuron firings.

The purpose of this letter is to expand a discussion, published recently in Molecular Immunology, on the post-secretion gain of function by immunoglobulins. It was reported that some circulating IgG molecules in all healthy individuals acquire novel antigen-binding specificity after exposure to conditions that change protein conformation, such as acidic pH. Another protein, C-reactive protein, also acquires novel ligand-binding specificity post-secretion after a switch from its native pentameric conformation to non-native pentameric conformation. Thus, that the functions of a protein depend upon its alternate structural states, and therefore on the surrounding milieu, is a more general phenomenon for some ancient molecules of the immune system than previously thought.

No description available.

Abstract: The nervous system and cardiovascular system develop in concert and are functionally interconnected in both health and disease. This white paper focuses on the cellular and molecular mechanisms that underlie neural–cardiac interactions during development, during normal physiological function in the mature system, and during pathological remodelling in cardiovascular disease. The content on each subject was contributed by experts, and we hope that this will provide a useful resource for newcomers to neurocardiology as well as aficionados.

No description available.

Ubiquitin (UB) is a highly conserved low molecular weight (8.5 kDa) protein. It consists of 76 amino acid residues and is found in all eukaryotic cells. The covalent linkage of UB to a variety of cellular proteins (ubiquitination) is one of the most common posttranslational modifications in eukaryotic cells. This modification generally regulates protein turnover and protects the cells from damaged or misfolded proteins. The polyubiquitination of proteins serves as a signal for degradation via the 26S proteasome pathway. UB is present in trace amounts in body fluids. Elevated levels of UB are described in the serum or plasma of patients under a variety of conditions. Extracellular UB is proposed to have pleiotropic roles including regulation of immune response, anti-inflammatory, and neuroprotective activities. CXCR4 is identified as receptor for extracellular UB in hematopoietic cells. Heart failure represents a major cause of morbidity and mortality in western society. Cardiac remodeling is a determinant of the clinical course of heart failure. The components involved in myocardial remodeling include-myocytes, fibroblasts, interstitium, and coronary vasculature. Increased sympathetic nerve activity in the form of norepinephrine is a common feature during heart failure. Acting via β-adrenergic receptor (β-AR), norepinephrine is shown to induce myocyte apoptosis and myocardial fibrosis. β-AR stimulation increases extracellular levels of UB in myocytes, and UB inhibits β-AR-stimulated increases in myocyte apoptosis and myocardial fibrosis. This review summarizes intracellular and extracellular functions of UB with particular emphasis on the role of extracellular UB in cardiac myocyte apoptosis and myocardial remodeling.

BDNF and its associated tropomyosin-related kinase receptor B (TrkB) nurture vessels and nerves serving the heart. However, the direct effect of BDNF/TrkB signaling on the myocardium is poorly understood. Here we report that cardiac-specific TrkB knockout mice (TrkB-/-) display impaired cardiac contraction and relaxation, showing that BDNF/TrkB signaling acts constitutively to sustain in vivo myocardial performance. BDNF enhances normal cardiomyocyte Ca2+ cycling, contractility, and relaxation via Ca2+/calmodulindependent protein kinase II (CaMKII). Conversely, failing myocytes, which have increased truncated TrkB lacking tyrosine kinase activity and chronically activated CaMKII, are insensitive to BDNF. Thus, BDNF/TrkB signaling represents a previously unidentified pathway by which the peripheral nervous system directly and tonically influences myocardial function in parallel with β-adrenergic control. Deficits in this system are likely additional contributors to acute and chronic cardiac dysfunction. BDNF TrkB receptorcardiac contractility/relaxation CaMKII neurotrophins We are grateful to Dr. David D. Ginty for providing us with TrkBF616A and TrkB conditional knockout mice.

Neurohumoral remodeling is fundamental to the evolution of heart disease. This study examined the effects of chronic treatment with an ACE inhibitor (captopril, 3 mg·kg_1·day_1), AT1 receptor antagonist (losartan, 3 mg·kg_1·day_1), or AT2 receptor agonist (CGP42112A, 0.14 mg·kg_1·day_1) on remodeling of the guinea pig intrinsic cardiac plexus following chronic myocardial infarction (MI). MI was surgically induced and animals recovered for 6 or 7 wk, with or without drug treatment. Intracellular voltage recordings from whole mounts of the cardiac plexus were used to monitor changes in neuronal responses to norepinephrine (NE), muscarinic agonists (bethanechol), or ANG II. MI produced an increase in neuronal excitability with NE and a loss of sensitivity to ANG II. MI animals treated with captopril exhibited increased neuronal excitability with NE application, while MI animals treated with CGP42112A did not. Losartan treatment of MI animals did not alter excitability with NE compared with untreated MIs, but these animals did show an enhanced synaptic efficacy. This effect on synaptic function was likely due to presynaptic AT1 receptors, since ANG II was able to reduce output to nerve fiber stimulation in control animals, and this effect was prevented by inclusion of losartan in the bath solution. Analysis of AT receptor expression by Western blot showed a decrease in both AT1 and AT2 receptors with MI that was reversed by all three drug treatments. These data indicate that neuronal remodeling of the guinea pig cardiac plexus following MI is mediated, in part, by activation of both AT1 and AT2 receptors.