Marginal zinc deficiency increases oxidative DNA damage in the prostate after chronic exercise

Approximately 12% of Americans do not consume the recommended level of zinc and could be at risk for marginal zinc deficiency. Zinc functions in antioxidant defense and DNA repair and could be important for prostate health. We hypothesized that marginal zinc deficiency sensitizes the prostate to oxidative stress and DNA damage. Rats were fed a zinc-adequate (ZA; 30 mg Zn/kg) or marginally zinc-deficient (MZD; 5–6 mg Zn/kg) diet for 6 weeks. MZD increased p53 and PARP expression but no change in 8-hydroxy-2′-deoxyguanosine levels was detected. To examine the susceptibility to exogenous oxidative stress, rats fed a ZA or MZD diet were assigned to exercising (EXE) or sedentary (SED) groups for 9 weeks. MZD or EXE alone did not affect oxidative DNA damage in the prostate; however, combined MZD + EXE increased DNA damage in the dorsolateral lobe. PARP and p53 expression was not further induced with MZD + EXE, suggesting that MZD interferes with DNA repair responses to stress. Finally, the addition of phytase to the MZD diet successfully restored zinc levels in the prostate and decreased DNA damage back to ZA levels. Overall, this study suggests that marginal zinc deficiency sensitizes the prostate to oxidative stress and demonstrates the importance of maintaining optimal zinc nutrition in physically active populations.     

Sensory information in local field potentials and spikes from visual and auditory cortices: time scales and frequency bands

Studies analyzing sensory cortical processing or trying to decode brain activity often rely on a combination of different electrophysiological signals, such as local field potentials (LFPs) and spiking activity. Understanding the relation between these signals and sensory stimuli and between different components of these signals is hence of great interest. We here provide an analysis of LFPs and spiking activity recorded from visual and auditory cortex during stimulation with natural stimuli. In particular, we focus on the time scales on which different components of these signals are informative about the stimulus, and on the dependencies between different components of these signals. Addressing the first question, we find that stimulus information in low frequency bands (<12 Hz) is high, regardless of whether their energy is computed at the scale of milliseconds or seconds. Stimulus information in higher bands (>50 Hz), in contrast, is scale dependent, and is larger when the energy is averaged over several hundreds of milliseconds. Indeed, combined analysis of signal reliability and information revealed that the energy of slow LFP fluctuations is well related to the stimulus even when considering individual or few cycles, while the energy of fast LFP oscillations carries information only when averaged over many cycles. Addressing the second question, we find that stimulus information in different LFP bands, and in different LFP bands and spiking activity, is largely independent regardless of time scale or sensory system. Taken together, these findings suggest that different LFP bands represent dynamic natural stimuli on distinct time scales and together provide a potentially rich source of information for sensory processing or decoding brain activity.     

Pulsed EPR investigations of the Mo(V) centers of the R55Q and R55M variants of sulfite dehydrogenase from Starkeya novella

Continuous-wave and pulsed electron paramagnetic resonance (EPR) spectroscopy have been used to characterize two variants of bacterial sulfite dehydrogenase (SDH) from Starkeya novella in which the conserved active-site arginine residue (R55) is replaced by a neutral amino acid residue. Substitution by the hydrophobic methionine residue (SDH^R55M) has essentially no effect on the pH dependence of the EPR properties of the Mo(V) center, even though the X-ray structure of this variant shows that the methionine residue is rotated away from the Mo center and a sulfate anion is present in the active-site pocket (Bailey et al. in J Biol Chem 284:2053–2063, 2009). For SDH^R55M only the high-pH form is observed, and samples prepared in H₂ ¹⁷O-enriched buffer show essentially the same ¹⁷O hyperfine interaction and nuclear quadrupole interaction parameters as SDH^WT enzyme. However, the pH dependence of the EPR spectra of SDH^R55Q, in which the positively charged arginine is replaced by the neutral hydrophilic glutamine, differs significantly from that of SDH^WT. For SDH^R55Q the blocked form with bound sulfate is generated at low pH, as verified by ³³S couplings observed upon reduction with ³³S-labeled sulfite. This observation of bound sulfate for SDH^R55Q supports our previous hypothesis that sulfite-oxidizing enzymes can exhibit multiple pathways for electron transfer and product release (Emesh et al. in Biochemistry 48:2156–2163, 2009). At pH ≥ 8 the high-pH form dominates for SDH^R55Q.     

Derivatives of tetrahydroisoquinoline: Synthesis and initial evaluation of novel non-peptide antagonists of the αIIbβ3-integrin

The novel RGDF mimetics were synthesized with the use of 4-(1,2,3,4-tetrahydroisoquinoline-7-yl)amino-4-oxobutyric or 5-(1,2,3,4-tetrahydroisoquinoline-7-yl)amino-5-oxopentanoic acids as a surrogate of Arg-Gly motif. The synthesized compounds have demonstrated a high potency to inhibit platelet aggregation in vitro and to block FITC-Fg binding to α_IIbβ₃ on washed human platelets.     

Synthesis and biological activity of 5-styryl and 5-phenethyl-substituted 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles

Syntheses, biological evaluation, and structure–activity relationships for a series of novel 5-styryl and 5-phenethyl analogs of dimebolin are disclosed. The novel derivatives and dimebolin share a broad spectrum of activities against therapeutically relevant targets. Among all synthesized derivatives, 2,8-dimethyl-5-[(Z)-2-phenylvinyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and its 5-phenethyl analog are the most potent blockers of 5-HT₇, 5-HT₆, 5-HT_2C, Adrenergic α₂ and H₁ receptors. The general affinity rank order towards the studied receptors was Z-3(2) > 4(2) ? 4(3) ? dimebolin, all of them having highest affinities to 5-HT₇ receptors.     

Linking ecology,morphology, and metabolism: Niche differentiation in sympatric populations of closely related species of the genus Littorina (Neritrema)

Divergence of ecological niches in phylogenetically closely related species indicates the importance of ecology in speciation, especially for sympatric species are considered. Such ecological diversification provides an advantage of alleviating interspecies competition and promotes more efficient exploitation of environmental resources, thus being a basis for ecological speciation. We analyzed a group of closely related species from the subgenus Neritrema (genus Littorina, Caenogastropoda) from the gravel‐bouldery shores. In two distant sites at the Barents and Norwegian Sea, we examined the patterns of snail distribution during low tide (quantitative sampling stratified by intertidal level, presence of macrophytes, macrophyte species, and position on them), shell shape and its variability (geometric morphometrics), and metabolic characteristics (metabolomic profiling). The studied species diversified microbiotopes, which imply an important role of ecological specification in the recent evolution of this group. The only exception to this trend was the species pair L. arcana / L. saxatilis, which is specifically discussed. The ecological divergence was accompanied by differences in shell shape and metabolomic characteristics. Significant differences were found between L. obtusata versus L. fabalis and L. saxatilis / L. arcana versus L. compressa both in shell morphology and in metabolomes. L. saxatilis demonstrated a clear variability depending on intertidal level which corresponds to a shift in conditions within the occupied microhabitat. Interestingly, the differences between L. arcana (inhabiting the upper intertidal level) and L. compressa (inhabiting the lower one) were analogous to those between the upper and lower fractions of L. saxatilis. No significant level‐dependent changes were found between the upper and lower fractions of L. obtusata, most probably due to habitat amelioration by fucoid macroalgae. All these results are discussed in the contexts of the role of ecology in speciation, ecological niche dynamics and conservatism, and evolutionary history of the Neritrema species.     

Structure and Mode-of-Action of the Two-Peptide (Class-IIb) Bacteriocins

This review focuses on the structure and mode-of-action of the two-peptide (class-IIb) bacteriocins that consist of two different peptides whose genes are next to each other in the same operon. Optimal antibacterial activity requires the presence of both peptides in about equal amounts. The two peptides are synthesized as preforms that contain a 15–30 residue double-glycine-type N-terminal leader sequence that is cleaved off at the C-terminal side of two glycine residues by a dedicated ABC-transporter that concomitantly transfers the bacteriocin peptides across cell membranes. Two-peptide bacteriocins render the membrane of sensitive bacteria permeable to a selected group of ions, indicating that the bacteriocins form or induce the formation of pores that display specificity with respect to the transport of molecules. Based on structure–function studies, it has been proposed that the two peptides of two-peptide bacteriocins form a membrane-penetrating helix–helix structure involving helix–helix-interacting GxxxG-motifs that are present in all characterized two-peptide bacteriocins. It has also been suggested that the membrane-penetrating helix–helix structure interacts with an integrated membrane protein, thereby triggering a conformational alteration in the protein, which in turn causes membrane-leakage. This proposed mode-of-action is similar to the mode-of-action of the pediocin-like (class-IIa) bacteriocins and lactococcin A (a class-IId bacteriocin), which bind to a membrane-embedded part of the mannose phosphotransferase permease in a manner that causes membrane-leakage and cell death.     

The C. elegans RSA complex localizes protein phosphatase 2A to centrosomes and regulates mitotic spindle assembly

Microtubule behavior changes during the cell cycle and during spindle assembly. However, it remains unclear how these changes are regulated and coordinated. We describe a complex that targets the Protein Phosphatase 2A holoenzyme (PP2A) to centrosomes in C. elegans embryos. This complex includes Regulator of Spindle Assembly 1 (RSA-1), a targeting subunit for PP2A, and RSA-2, a protein that binds and recruits RSA-1 to centrosomes. In contrast to the multiple functions of the PP2A catalytic subunit, RSA-1 and RSA-2 are specifically required for microtubule outgrowth from centrosomes and for spindle assembly. The centrosomally localized RSA-PP2A complex mediates these functions in part by regulating two critical mitotic effectors: the microtubule destabilizer KLP-7 and the C. elegans regulator of spindle assembly TPXL-1. By regulating a subset of PP2A functions at the centrosome, the RSA complex could therefore provide a means of coordinating microtubule outgrowth from centrosomes and kinetochore microtubule stability during mitotic spindle assembly.     

Global Properties of Infectious Disease Models with Nonlinear Incidence

We consider global properties for the classical SIR, SIRS and SEIR models of infectious diseases, including the models with the vertical transmission, assuming that the horizontal transmission is governed by an unspecified function f(S,I). We construct Lyapunov functions which enable us to find biologically realistic conditions sufficient to ensure existence and uniqueness of a globally asymptotically stable equilibrium state. This state can be either endemic, or infection-free, depending on the value of the basic reproduction number.     

Bcl-2 and Bcl-XL regulate proinflammatory caspase-1 activation by interaction with NALP1

Caspases are intracellular proteases that cleave substrates involved in apoptosis or inflammation. In C. elegans, a paradigm for caspase regulation exists in which caspase CED-3 is activated by nucleotide-binding protein CED-4, which is suppressed by Bcl-2-family protein CED-9. We have identified a mammalian analog of this caspase-regulatory system in the NLR-family protein NALP1, a nucleotide-dependent activator of cytokine-processing protease caspase-1, which responds to bacterial ligand muramyl-dipeptide (MDP). Antiapoptotic proteins Bcl-2 and Bcl-X(L) bind and suppress NALP1, reducing caspase-1 activation and interleukin-1beta (IL-1beta) production. When exposed to MDP, Bcl-2-deficient macrophages exhibit more caspase-1 processing and IL-1beta production, whereas Bcl-2-overexpressing macrophages demonstrate less caspase-1 processing and IL-1beta production. The findings reveal an interaction of host defense and apoptosis machinery.