Compound motor action potentials in transient and persistent phrenic nerve injury - metanalysis.

The right phrenic nerve is vulnerable to injury (PNI) during cryoballoon ablation (CBA) isolation of the right pulmonary veins. The complication can be transient or persistent. The reported incidence of PNI fluctuates from 4.

Immunoediting role for major vault protein in apoptotic signaling induced by bacterial -acyl homoserine lactones.

The major vault protein (MVP) mediates diverse cellular responses, including cancer cell resistance to chemotherapy and protection against inflammatory responses to Here, we report the use of photoactive probes to identify MVP as a target of the -(3-oxo-dodecanoyl) homoserine lactone (C12), a quorum sensing signal of certain proteobacteria including A treatment of normal and cancer cells with C12 or other -acyl homoserine lactones (AHLs) results in rapid translocation of MVP into lipid raft (LR) membrane fractions. Like AHLs, inflammatory stimuli also induce LR-localization of MVP, but the C12 stimulation reprograms (functionalizes) bioactivity of the plasma membrane by recruiting death receptors, their apoptotic adaptors, and caspase-8 into LR. These functionalized membranes control AHL-induced signaling processes, in that MVP adjusts the protein kinase p38 pathway to attenuate programmed cell death.

A synthetic opioid vaccine attenuates fentanyl-vs-food choice in male and female rhesus monkeys.

Aim: Opioid-targeted vaccines are under consideration as candidate Opioid Use Disorder medications. We recently reported that a fentanyl-targeted vaccine produced a robust and long-lasting attenuation of fentanyl-vs-food choice in rats. In the current study, we evaluated an optimized fentanyl-targeted vaccine in rhesus monkeys to determine whether vaccine effectiveness to attenuate fentanyl choice translated to a species with greater phylogenetic similarity to humans.

Synthetic molecules for disruption of the MYC protein-protein interface.

MYC is a key transcriptional regulator involved in cellular proliferation and has established roles in transcriptional elongation and initiation, microRNA regulation, apoptosis, and pluripotency. Despite this prevalence, functional chemical probes of MYC function at the protein level have been limited. Previously, we discovered 5a, that binds to MYC with potency and specificity, downregulates the transcriptional activities of MYC and shows efficacy in vivo.

Mining a Kröhnke Pyridine Library for Anti-Arenavirus Activity.

Several arenaviruses cause hemorrhagic fever (HF) disease in humans and represent important public health problems in their endemic regions. In addition, evidence indicates that the worldwide-distributed prototypic arenavirus lymphocytic choriomeningitis virus is a neglected human pathogen of clinical significance. There are no licensed arenavirus vaccines, and current antiarenavirus therapy is limited to an off-label use of ribavirin that is only partially effective.

A bioconjugate leveraging xenoreactive antibodies to alleviate cocaine-induced behavior.

A method for potentiating the response to an anti-cocaine vaccine by leveraging xenoreactive antibodies against the carbohydrate epitope Galα1,3-Gal (GAL) was found to result in a highly specific anti-cocaine response that was able to significantly attenuate cocaine-induced locomotion at 20 mg kg with superior efficacy compared to a standard conjugate.

The design and synthesis of an α-Gal trisaccharide epitope that provides a highly specific anti-Gal immune response.

Carbohydrate antigens displaying Galα(1,3)Gal epitopes are recognized by naturally occurring antibodies in humans. These anti-Gal antibodies comprise up to 1% of serum IgG and have been viewed as detrimental as they are responsible for hyperacute organ rejections. In order to model this condition, α(1,3)galactosyltransferase-knockout mice are inoculated against the Galα(1,3)Gal epitope.

Studies towards the improvement of an anti-cocaine monoclonal antibody for treatment of acute overdose.

There is currently no clinically-approved antidote for cocaine overdose. Efforts to develop a therapy via passive immunization have resulted in a human monoclonal antibody, GNCgzk, with a high affinity for cocaine (K=0.18nM).

Investigations of Enantiopure Nicotine Haptens Using an Adjuvanting Carrier in Anti-Nicotine Vaccine Development.

Despite efforts to produce suitable smoking cessation aids, addiction to nicotine continues to carry a substantive risk of recidivism. An attractive alternative to current therapies is the pharmacokinetic strategy of antinicotine vaccination. A major hurdle in the development of the strategy has been to elicit a sufficiently high antibody concentration to curb nicotine distribution to the brain.

Ribosomal Synthesis of Macrocyclic Peptides in Vitro and in Vivo Mediated by Genetically Encoded Aminothiol Unnatural Amino Acids.

A versatile method for orchestrating the formation of side chain-to-tail cyclic peptides from ribosomally derived polypeptide precursors is reported. Upon ribosomal incorporation into intein-containing precursor proteins, designer unnatural amino acids bearing side chain 1,3- or 1,2-aminothiol functionalities are able to promote the cyclization of a downstream target peptide sequence via a C-terminal ligation/ring contraction mechanism. Using this approach, peptide macrocycles of variable size and composition could be generated in a pH-triggered manner in vitro or directly in living bacterial cells.

Pharmacophore reassignment for induction of the immunosurveillance cytokine TRAIL.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is an immunosurveillance cytokine that kills cancer cells but demonstrates little toxicity against normal cells. While investigating the TRAIL-inducing imidazolinopyrimidinone TIC10, a misassignment of its active structure was uncovered. Syntheses of the two isomers, corresponding to the published and reassigned structures, are reported.

Complex biventricular pacing - a case series.

It is established that cardiac resynchronisation therapy (CRT) reduces mortality and hospitalisation and improves functional class in patients with NYHA class 3-4 heart failure, an ejection fraction of ≤ 35% and a QRS duration of ≥ 120ms. Recent updates in the American guidelines have expanded the demographic of patients in whom CRT may be appropriate. Here we present two cases of complex CRT; one with a conventional indication but occluded central veins and the second with a novel indication for CRT post cardiac transplant.

Macrocyclization of organo-peptide hybrids through a dual bio-orthogonal ligation: insights from structure-reactivity studies.

Macrocycles constitute an attractive structural class of molecules for targeting biomolecular interfaces with high affinity and specificity. Here, we report systematic studies aimed at exploring the scope and mechanism of a novel chemo-biosynthetic strategy for generating macrocyclic organo-peptide hybrids (MOrPHs) through a dual oxime-/intein-mediated ligation reaction between a recombinant precursor protein and bifunctional, oxyamino/1,3-amino-thiol compounds. An efficient synthetic route was developed to access structurally different synthetic precursors incorporating a 2-amino- mercaptomethyl-aryl (AMA) moiety previously found to be important for macrocyclization.