Polyalcohol ligand in Cu and Fe cluster chemistry: Synthesis, structures and magnetic properties of {Cu12} and {Fe8} aggregates

Structurally unique {Cu₁₂} and {Fe₈} cluster complexes were synthesized using 2,2,6,6-tetrakis (hydroxymethyl)cyclohexanol (thcH₅) ligand. The polyalcohol thcH₅ ligand consists of a six membered ring in a chair confirmation and five pendant alcohol arms providing pentadentate-anchoring points for coordination chemistry. A wide range of reaction conditions was explored with transition metal ions in order to isolate large cluster complexes. Obtained {Cu₁₂} and {Fe₈} complexes exhibit unprecedented core topologies where thcH₅ encapsulate and bridge between metal centers and mediate magnetic interactions via the superexchange pathways. Both complexes exhibit dominant intramolecular antiferromagnetic interactions leading to singlet spin ground state.     

Ebolavirus delta-peptide immunoadhesins inhibit marburgvirus and ebolavirus cell entry

With the exception of Reston and Lloviu viruses, filoviruses (marburgviruses, ebolaviruses, and “cuevaviruses”) cause severe viral hemorrhagic fevers in humans. Filoviruses use a class I fusion protein, GP_1,2, to bind to an unknown, but shared, cell surface receptor to initiate virus-cell fusion. In addition to GP_1,2, ebolaviruses and cuevaviruses, but not marburgviruses, express two secreted glycoproteins, soluble GP (sGP) and small soluble GP (ssGP). All three glycoproteins have identical N termini that include the receptor-binding region (RBR) but differ in their C termini. We evaluated the effect of the secreted ebolavirus glycoproteins on marburgvirus and ebolavirus cell entry, using Fc-tagged recombinant proteins. Neither sGP-Fc nor ssGP-Fc bound to filovirus-permissive cells or inhibited GP_1,2-mediated cell entry of pseudotyped retroviruses. Surprisingly, several Fc-tagged Δ-peptides, which are small C-terminal cleavage products of sGP secreted by ebolavirus-infected cells, inhibited entry of retroviruses pseudotyped with Marburg virus GP_1,2, as well as Marburg virus and Ebola virus infection in a dose-dependent manner and at low molarity despite absence of sequence similarity to filovirus RBRs. Fc-tagged Δ-peptides from three ebolaviruses (Ebola virus, Sudan virus, and Taï Forest virus) inhibited GP_1,2-mediated entry and infection of viruses comparably to or better than the Fc-tagged RBRs, whereas the Δ-peptide-Fc of an ebolavirus nonpathogenic for humans (Reston virus) and that of an ebolavirus with lower lethality for humans (Bundibugyo virus) had little effect. These data indicate that Δ-peptides are functional components of ebolavirus proteomes. They join cathepsins and integrins as novel modulators of filovirus cell entry, might play important roles in pathogenesis, and could be exploited for the synthesis of powerful new antivirals.     

Predictive algorithms for adjuvant therapy: TransATAC

Estrogen receptor (ER) positive primary breast cancers have a wide range of clinical outcomes. Prediction of the likely course of the disease aids treatment decision-making. In the translational arm of the ATAC (anastrozole or tamoxifen alone or combined) trial (TransATAC) we have assessed individual and multiparameter biomarkers for their prediction of overall and distant recurrence. None of the biomarkers identified differential benefit for anastrozole versus tamoxifen. Each of ER, PgR, HER2 and Ki67 was associated with risk of recurrence. A combination of these to create a single predictor IHC4 was as informative as the 21-gene recurrence score (RS). Integration of each of these molecular profiles with classical clinicopathologic variables provided the most accurate prediction of outcome.     

A new oviposition deterrent to the leafminer, Liriomyza trifolii: cucurbitane glucoside from Momordica charantia

A new cucurbitane glucoside, 23-O-beta-D-glucopyranosyl-7-hydroxy-3-O-malonylcucurbita-5,24-dien-19-al, named momordicine V, has been isolated from Momordica charantia leaves, along with the previously reported compounds, momordicines I, II, IV and 3-O-malonylmomordicine I. The structure of the new compound was established on the basis of spectral analysis, as well as by its conversion to momordicine II by alkaline catalyzed hydrolysis. Momordicine V deterred significantly the oviposition by L. trifolii on host plant leaves treated at 26.16 microg/cm2 leaf surface.     

Subunit dependence of Na channel slow inactivation and open channel block in cerebellar neurons

Purkinje and cerebellar nuclear neurons both have Na currents with resurgent kinetics. Previous observations, however, suggest that their Na channels differ in their susceptibility to entering long-lived inactivated states. To compare fast inactivation, slow inactivation, and open-channel block, we recorded voltage-clamped, tetrodotoxin-sensitive Na currents in Purkinje and nuclear neurons acutely isolated from mouse cerebellum. In nuclear neurons, recovery from all inactivated states was slower, and open-channel unblock was less voltage-dependent than in Purkinje cells. To test whether specific subunits contributed to this differential stability of inactivation, experiments were repeated in Na(V)1.6-null (med) mice. In med Purkinje cells, recovery times were prolonged and the voltage dependence of open-channel block was reduced relative to control cells, suggesting that availability of Na(V)1.6 is quickly restored at negative potentials. In med nuclear cells, however, currents were unchanged, suggesting that Na(V)1.6 contributes little to wild-type nuclear cells. Extracellular Na(+) prevented slow inactivation more effectively in Purkinje than in nuclear neurons, consistent with a resilience of Na(V)1.6 to slow inactivation. The tendency of nuclear Na channels to inactivate produced a low availability during trains of spike-like depolarization. Hyperpolarizations that approximated synaptic inhibition effectively recovered channels, suggesting that increases in Na channel availability promote rebound firing after inhibition.     

Role of purinergic receptors in hepatobiliary carcinoma in Pakistani population: an approach towards proinflammatory role of P2X4 and P2X7 receptors

Purinergic Signalling - The primary malignancy of liver, known as hepatocellular carcinoma (HCC), comprises 9% of all hepatobiliary carcinomas. A steady rise has also been observed in...     

A rabbit ventricular action potential model replicating cardiac dynamics at rapid heart rates

Mathematical modeling of the cardiac action potential has proven to be a powerful tool for illuminating various aspects of cardiac function, including cardiac arrhythmias. However, no currently available detailed action potential model accurately reproduces the dynamics of the cardiac action potential and intracellular calcium (Ca_i) cycling at rapid heart rates relevant to ventricular tachycardia and fibrillation. The aim of this study was to develop such a model. Using an existing rabbit ventricular action potential model, we modified the L-type calcium (Ca) current (I_Ca,L) and Ca_i cycling formulations based on new experimental patch-clamp data obtained in isolated rabbit ventricular myocytes, using the perforated patch configuration at 35-37°C. Incorporating a minimal seven-state Markovian model of I_Ca,L that reproduced Ca- and voltage-dependent kinetics in combination with our previously published dynamic Ca_i cycling model, the new model replicates experimentally observed action potential duration and Ca_i transient alternans at rapid heart rates, and accurately reproduces experimental action potential duration restitution curves obtained by either dynamic or S1S2 pacing.     

An evaluation of information content as a metric for the inference of putative conserved noncoding regions in DNA sequences using a genetic algorithms approach

In previous work, we presented GAMI, an approach to motif inference that uses a genetic algorithms search. GAMI is designed specifically to find putative conserved regulatory motifs in noncoding regions of divergent species, and is designed to allow for analysis of long nucleotide sequences. In this work, we compare GAMI's performance when run with its original fitness function (a simple count of the number of matches) and when run with information content, as well as several variations on these metrics. Results indicate that information content does not identify highly conserved regions, and thus is not the appropriate metric for this task, while variations on information content as well as the original metric succeed in identifying putative conserved regions.