The Glycosylation of AGP and Its Associations with the Binding to Methadone

Methadone remains the most common form of pharmacological therapy for opioid dependence; however, there is a lack ofexplanation for the reports of its relatively low success rate in achieving complete abstinence. One hypothesis is that in vivo bindingof methadone to the plasma glycoprotein alpha-1-acid glycoprotein (AGP), to a degree dependent on the molecular structure,may render the drug inactive. This study sought to determine whether alterations present in the glycosylation pattern of AGP inpatients undergoing various stages of methadone therapy (titration one anda half years) could affect the affinity of the glycoprotein to bind methadone. The composition of AGP glycosylation was determinedusing high pH anion exchange chromatography (HPAEC) and intrinsic fluorescence analysed to determine the extent of binding tomethadone. The monosaccharides galactose and N-acetyl-glucosamine were elevated in all methadone treatment groups indicatingalterations in AGP glycosylation. AGP from all patients receiving methadone therapy exhibited a greater degree of binding than thenormal population. This suggests that analysing the glycosylation of AGP in patients receiving methadone may aid in determiningwhether the therapy is likely to be effective

Facet-dependent interactions of islet amyloid polypeptide with gold nanoparticles: implications for fibril formation and peptide-induced lipid membrane disruption

A comprehensive understanding of the mechanisms of interaction between proteins or peptides and nanomaterials is crucial for the development of nanomaterial-based diagnos-tics and therapeutics. In this work, we systematically explored the interactions between citrate-capped gold nanoparticles (AuNPs) and islet amyloid polypeptide (IAPP), a 37-amino acid peptide hormone co-secreted with insulin from the pancreatic islet. We uti-lized diffusion-ordered spectroscopy, isothermal titration calorimetry, localized surface plasmon resonance spectroscopy, gel electrophoresis, atomic force microscopy, transmis-sion electron microscopy (TEM), and molecular dynamics (MD) simulations to systemati-cally elucidate the underlying mechanism of the IAPP−AuNP interactions. Because of the presence of a metal-binding sequence motif in the hydrophilic peptide domain, IAPP strongly interacts with the Au surface in both the monomeric and fibrillar states. Circular dichroism showed that AuNPs triggered the IAPP conformational transition from random coil to ordered structures (α-helix and β-sheet), and TEM imaging suggested the accelera-tion of IAPP fibrillation in the presence of AuNPs. MD simulations revealed that the IAPP−AuNP interactions were initiated by the N-terminal domain (IAPP residues 1−19), which subsequently induced a facet-dependent conformational change in IAPP. On a Au(111) surface, IAPP was unfolded and adsorbed directly onto the Au surface, while for the Au(100) surface, it interacted predominantly with the citrate adlayer and retained some helical conformation. The observed affinity of AuNPs for IAPP was further applied to reduce the level of peptide-induced lipid membrane disruption

Facet-dependent interactions of islet amyloid polypeptide with gold nanoparticles: Implications for fibril formation and peptide-induced lipid membrane disruption

A comprehensive understanding of the mechanisms of interaction between proteins or peptides and nanomaterials is crucial for the development of nanomaterial-based diagnostics and therapeutics. In this work, we systematically explored the interactions between citrate-capped gold nanoparticles (AuNPs) and islet amyloid polypeptide (IAPP), a 37-amino acid peptide hormone co-secreted with insulin from the pancreatic islet. We utilized diffusion-ordered spectroscopy, isothermal titration calorimetry, localized surface plasmon resonance spectroscopy, gel electrophoresis, atomic force microscopy, transmission electron microscopy (TEM), and molecular dynamics (MD) simulations to systematically elucidate the underlying mechanism of the IAPP–AuNP interactions. Because of the presence of a metal-binding sequence motif in the hydrophilic peptide domain, IAPP strongly interacts with the Au surface in both the monomeric and fibrillar states. Circular dichroism showed that AuNPs triggered the IAPP conformational transition from random coil to ordered structures (α-helix and β-sheet), and TEM imaging suggested the acceleration of IAPP fibrillation in the presence of AuNPs. MD simulations revealed that the IAPP–AuNP interactions were initiated by the N-terminal domain (IAPP residues 1–19), which subsequently induced a facet-dependent conformational change in IAPP. On a Au(111) surface, IAPP was unfolded and adsorbed directly onto the Au surface, while for the Au(100) surface, it interacted predominantly with the citrate adlayer and retained some helical conformation. The observed affinity of AuNPs for IAPP was further applied to reduce the level of peptide-induced lipid membrane disruption

Ears of the Armadillo: Global Health Research and Neglected Diseases in Texas

Neglected tropical diseases (NTDs) have\ud been recently identified as significant public\ud health problems in Texas and elsewhere in\ud the American South. A one-day forum on the\ud landscape of research and development and\ud the hidden burden of NTDs in Texas\ud explored the next steps to coordinate advocacy,\ud public health, and research into a\ud cogent health policy framework for the\ud American NTDs. It also highlighted how\ud U.S.-funded global health research can serve\ud to combat these health disparities in the\ud United States, in addition to benefiting\ud communities abroad

PenQuest Volume 2, Number 1

Table of Contents for this Volume: Untitled by Janet Collins Untitled by Judy Gozdur Last Hour of Light by Susan Reed Untitled by Judy Godzur Untitled by Rick Wagner Untitled by Carol Groover Untitled by R. Wagner Only in the Portico by Linda Banicki Untitled by Helen Hagadorn Private Place, Pubic Place by David Reed Untitled by Tammy Hutchinson Untitled by Tammy Hutchinson Madison Knights by Susan Reed Untitled by Sissy Crabtree The Price by Sandra Coleman Untitled by Ann Harrington Invasion of Privacy by Mark Touchton Untitled by Bruce Warner Untitled by Tom Schifanella Untitled by Tammy Hutchinson Bloodwork by Laura Jo Last Untitled by David Whitsett Burial Instructions by Bill Slaughter Untitled by S. Trevett PenQuest Interview: Joe Haldeman by David Reed Her Name Came from the Sea by Richard L. Ewart Untitled by V. Williams In the Woodshed by R. E. Mallery Untitled by Modesta Matthews Untitled by David Olson Illumination by E. Allen Tilley Untitled by Joseph Avanzini Everywoman by Laura Jo Last Untitled by Beth Goeckel Believe Me by Donna Kaluzniak Untitled by Judy Gozdur Untitled by Judy Gozdur Unicorn by David Reed Untitled by Susan Reed untitled by Paul Cramer Unititled by Lucinda Halsema The Violin by Richard L. Ewart Untitled by Maria Barry Untitled by Roger Whitt Jr. Haiku by Lori Nasrallah Rhymer’s Revolt by R. E. Mallery Untitled by Valerie William

Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis

Multiple sclerosis (MS), a chronic disorder of the central nervous system and common cause of neurological disability in young adults, is characterized by moderate but complex risk heritability. Here we report the results of a genome-wide association study performed in a 1000 prospective case series of well-characterized individuals with MS and group-matched controls using the Sentrix® HumanHap550 BeadChip platform from Illumina. After stringent quality control data filtering, we compared allele frequencies for 551 642 SNPs in 978 cases and 883 controls and assessed genotypic influences on susceptibility, age of onset, disease severity, as well as brain lesion load and normalized brain volume from magnetic resonance imaging exams. A multi-analytical strategy identified 242 susceptibility SNPs exceeding established thresholds of significance, including 65 within the MHC locus in chromosome 6p21.3. Independent replication confirms a role for GPC5, a heparan sulfate proteoglycan, in disease risk. Gene ontology-based analysis shows a functional dichotomy between genes involved in the susceptibility pathway and those affecting the clinical phenotyp

Measurement of the cosmic ray spectrum above 4×10184{\times}10^{18} eV using inclined events detected with the Pierre Auger Observatory

A measurement of the cosmic-ray spectrum for energies exceeding $4{\times}10^{18}$ eV is presented, which is based on the analysis of showers with zenith angles greater than $60^{\circ}$ detected with the Pierre Auger Observatory between 1 January 2004 and 31 December 2013. The measured spectrum confirms a flux suppression at the highest energies. Above $5.3{\times}10^{18}$ eV, the "ankle", the flux can be described by a power law $E^{-\gamma}$ with index $\gamma=2.70 \pm 0.02 \,\text{(stat)} \pm 0.1\,\text{(sys)}$ followed by a smooth suppression region. For the energy ($E_\text{s}$) at which the spectral flux has fallen to one-half of its extrapolated value in the absence of suppression, we find $E_\text{s}=(5.12\pm0.25\,\text{(stat)}^{+1.0}_{-1.2}\,\text{(sys)}){\times}10^{19}$ eV.Comment: Replaced with published version. Added journal reference and DO