Altered Cortical Oscillations: Investigations into a Putative Neural Correlate of Tinnitus

Abnormal cortical oscillations have been implicated in tinnitus generation. To gain further insight into this relationship, we performed two Experimental Series, both employing behavioural, pharmacological, and in vivo electrophysiological techniques in an animal model. To that end, we revealed three novel findings: (1) While exposure to 250 mg/kg sodium salicylate or transient loud noise induced behavioural evidence of tinnitus, these insults caused dissimilar effects on spontaneous cortical oscillations; (2) Despite these dissimilar effects, sodium salicylate and loud noise exposure caused similar deficits in the evoked oscillatory activity elicited by the auditory steady state response; and (3) Manipulation of medial geniculate body GABAergic inhibition is sufficient to alter spontaneous cortical oscillations, but does not induce tinnitus-like behaviour. Collectively, these findings suggest that there is no clear link between altered cortical oscillations and tinnitus, and the 40 Hz ASSR might be a useful tool for assessing the presence of tinnitus in animals

Metal Ion-Coordinating Properties in Aqueous Solution of the Antivirally Active Nucleotide Analogue (S)-9-[3-Hydroxy-2-(phosphonomethoxy)propyl]adenine (HPMPA). Quantification of Complex Isomeric Equilibria

Acyclic nucleoside phosphonates are of medical relevance and deserve detailed chemical characterization. We focus here on ( S )‐9‐[3‐hydroxy‐2‐(phosphonomethoxy)propyl]adenine (HPMPA) and include for comparison 9‐[2‐(phosphonomethoxy)ethyl]adenine (PMEA), as well as the nucleobase‐free (phosphonomethoxy)ethane (PME) and ( R )‐hydroxy‐2‐(phosphonomethoxy)propane (HPMP). The acidity constants of H 3 (HPMPA) + were determined and compared with those of the related phosph(on)ate derivatives; they are also needed to understand the properties of the metal ion complexes. Given that in vivo nucleotides and their analogues participate in reactions typically as divalent metal ion (M 2+ ) complexes, the stability constants of the M(H;HPMPA) + and M(HPMPA) species with M 2+ = Mg 2+ , Ca 2+ , Sr 2+ , Ba 2+ , Mn 2+ , Co 2+ , Ni 2+ , Cu 2+ , Zn 2+ , and Cd 2+ were measured. Comparisons between the results for HPMPA 2- and the previous data for PMEA 2- , HPMP 2- and PME 2- revealed that for most M(HPMPA) complexes the enhanced stability (the enhancement relative to the stability of a simple phosphonate‐M 2+ coordination), can solely be explained by the formation of 5‐membered chelates involving the ether oxygen. These chelates occur in equilibrium with simple ′open′ phosphonate‐M 2+ species, the phosphonate group being the primary binding site. The only exceptions are the M(HPMPA) complexes of Ni 2+ , Cu 2+ , and Zn 2+ , which show an additional stability enhancement; in these instances not only the indicated 5‐membered chelates are formed, but M 2+ coordinates in addition to N3 of the adenine residue forming a 7‐membered chelate ring. This observation regarding N3 is important because it emphasizes the metal ion affinity of this site (which is often ignored). Note that in the DNA double helix N3 is exposed to the solvent in the minor groove. The stability data for the monoprotonated M(H;HPMPA) + complexes suggest that these carry H + at the phosphonate group whereas M 2+ is partly at the nucleobase and partly also at the phosphonate group. The ratios of these isomers depend on the metal ion involved, e.g., for Cu(H;HPMPA) the ratio of the isomers is about 1:1

Comments on spin operators and spin-polarization states of 2+1 fermions

In this brief article we discuss spin polarization operators and spin polarization states of 2+1 massive Dirac fermions and find a convenient representation by the help of 4-spinors for their description. We stress that in particular the use of such a representation allows us to introduce the conserved covariant spin operator in the 2+1 field theory. Another advantage of this representation is related to the pseudoclassical limit of the theory. Indeed, quantization of the pseudoclassical model of a spinning particle in 2+1 dimensions leads to the 4-spinor representation as the adequate realization of the operator algebra, where the corresponding operator of a first-class constraint, which cannot be gauged out by imposing the gauge condition, is just the covariant operator previously introduced in the quantum theory.Comment: 6 page

Metal Ion Complexes of Nuceloside Phosphorothioates Reflecting the Ambivalent Properties of Lead (II)

This Perspective outlines the coordinating properties of lead( II ), to some extent in comparison with related metal ions like Ca 2+ , Zn 2+ or Cd 2+ . It is worth noting that the affinity of Pb 2+ towards phosphate residues corresponds to that of Cu 2+ . Furthermore, the binding tendency of Pb 2+ towards thiophosphate groups as present in methyl thiophosphate (MeOPS 2− ) or uridine 5′- O -thiomonophosphate (UMPS 2− ) is compared with that of the parent ligands, that is, methyl phosphate (CH 3 OPO 3 2− ) and uridine 5′-monophosphate (UMP 2− ). The replacement of an O by a S atom makes the monoprotonated thiophosphate group considerably more acidic [compared to ROP(O) 2 − (OH)], but at the same time its affinity for Pb 2+ increases tremendously: more than 99% of Pb 2+ is S-bound. This is very different if the coordinating properties of uridylyl-(5′→3′)-[5′]-uridylate (pUpU 3− ) and P -thiouridylyl-(5′→3′)-[5′]-uridylate (pUp (S) U 3− ) are compared. The phosphate-coordinated Pb 2+ forms a 10-membered chelate with one of the two terminal O atoms of the phosphodiester linkage, which reaches a formation degree of about 90% in Pb(pUpU) − . However, in Pb(pUp (S) U) − the formation degree of the chelate is reduced to about half in accordance with the fact that now only one terminal O atom is available in the thiophosphate diester bridge, that is, Pb 2+ coordinates to this O showing no affinity for S in ROP(O)(S) − OR′. These observations are ascribed to the properties of the Pb 2+ lone pair, which shapes the Pb 2+ coordination sphere; its role is discussed further in this Perspective and a caveat is made regarding Pb 2+ binding to a thiophosphate diester linkage

Extent of intramolecular π stacks in aqueous solution in mixed-ligand copper(II) complexes formed by heteroaromatic amines and the anticancer and antivirally active 9-[2-phosphonomethoxy)ethyl]guanine (PMEG).✩ a comparison with related acyclic nucleotide analogues

The acyclic nucleoside phosphonate (ANP2– ) 9-[2-(phosphonomethoxy)ethyl]guanine (PMEG) is anticancer and antivirally active. The acidity constants of the threefold protonated H3(PMEG)+ were determined by potentiometric pH titrations (aq. sol.; 25°C; I = 0.1 M, NaNO3). Under the same conditions and by the same method, the stability constants of the binary Cu(H;PMEG)+ and Cu(PMEG) complexes as well as those of the ternary ones containing a heteroaromatic N ligand (Arm), that is, of Cu(Arm)(H;PMEG)+ and Cu(Arm)(PMEG), where Arm = 2,2'-bipyridine (Bpy) or 1,10-phenanthroline (Phen), were measured. The corresponding equilibrium constants, taken from our earlier work for the systems with 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) and 9-[2-(phosphonomethoxy)ethyl]-2,6-diamino-purine (PMEDAP) as well as those for Cu(PME) and Cu(Arm)(PME), where PME2– = (phosphonomethoxy)ethane = (ethoxymethyl)phosphonate, were used for comparisons. These reveal that in the monoprotonated ternary Cu(Arm)(H;PE)+ complexes, the proton and Cu(Arm)2+ are at the phosphonate group; the ether oxygen of the -CH2-O-CH2-P(O) 2 ! (OH) residue also participates to some extent in Cu(Arm)2+ coordination. Furthermore, the coordinated Cu(Arm)2+ forms a bridge with the purine moiety undergoing π-π stacking which is more pronounced with H·PMEDAP– than with H·PMEA– . Most intense is π stack formation (st) with the guanine residue of H·PMEG– ; here the bridged form Cu(Arm)(H·PMEG) st + occurs next to an open (op), unbridged (binary) stack, formulated as Cu(Arm)2+/(H·PMEG) op ! . – The unprotonated and neutral ternary Cu(Arm)(PE) complexes are considerably more stable than the corresponding Cu(Arm)(R-PO3) species, where R-PO3 2! represents a phosph(on)ate ligand with a group R that is unable to participate in any intramolecular interaction. The observed stability enhancements are mainly due to intramolecular stack formation (st) between the aromatic rings of Arm and the purine residue in the Cu(Arm)(PE) complexes and also, to a smaller extent, to the formation of fivemembered chelates involving the ether oxygen of the -CH2-O-CH2-PO 3 2! residue (cl/O) of the PE2– species. The quantitative analysis of the intramolecular equilibria reveals three structurally different Cu(Arm)(PE) isomers; e.g., of Cu(Phen)(PMEG) ca. 1.1% exist as Cu(Phen)(PMEG)op, 3.5% as Cu(Phen)(PMEG)cl/O, and 95% as Cu(Phen)(PMEG)st. Comparison of the various 3 formation degrees reveals that within a given Cu(Arm)(PE) series the stacking tendency decreases in the order PMEG2– ≥ PMEDAP2– > PMEA2– . Furthermore, stacking is more pronounced in the acyclic Cu(Arm)(PE) complexes compared with that in the Cu(Arm)(NMP) species, where NMP2– = corresponding parent (2'-deoxy)nucleoside 5'-monophosphate. Here is possibly one of the reasons for the biological activity of the ANPs. One is tempted to speculate that the pronounced stacking tendency of PMEG2– , together with a different H-bonding pattern, leads to enhanced binding in the active site of nucleic acid polymerases, thus being responsible for the pronounced anticancer and antiviral activity of PMEG

Pancreatoblastoma: Cytologic and histologic analysis of 12 adult cases reveals helpful criteria in their diagnosis and distinction from common mimics

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152894/1/cncy22187_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/152894/2/cncy22187.pd

A Model for the Evolution of Nucleotide Polymerase Directionality

Background: In all known living organisms, every enzyme that synthesizes nucleic acid polymers does so by adding nucleotide 59-triphosphates to the 39-hydroxyl group of the growing chain. This results in the well known 5’?3’ directionality of all DNA and RNA Polymerases. The lack of any alternative mechanism, e.g. addition in a 3’?5 ’ direction, may indicate a very early founder effect in the evolution of life, or it may be the result of a selective pressure against such an alternative. Methodology/Principal Findings: In an attempt to determine whether the lack of an alternative polymerase directionality is the result of a founder effect or evolutionary selection, we have constructed a basic model of early polymerase evolution. This model is informed by the essential chemical properties of the nucleotide polymerization reaction. With this model, we are able to simulate the growth of organisms with polymerases that synthesize either 5’?3 ’ or 3’?5 ’ in isolation or in competition with each other. Conclusions/Significance: We have found that a competition between organisms with 5’?3 ’ polymerases and 3’?5’ polymerases only results in a evolutionarily stable strategy under certain conditions. Furthermore, we have found that mutations lead to a much clearer delineation between conditions that lead to a stable coexistence of these populations and conditions which ultimately lead to success for the 5’?3 ’ form. In addition to presenting a plausible explanation for th