Ligand Valency Affects Transcytosis, Recycling and Intracellular Trafficking Mediated by the Neonatal Fc Receptor

The neonatal Fc receptor (FcRn) transports IgG across epithelial cell barriers to provide maternal antibodies to offspring and serves as a protection receptor by rescuing endocytosed IgG and albumin from lysosomal degradation. Here we describe the generation of polarized Madin–Darby canine kidney (MDCK) cells expressing rat FcRn (rFcRn) to investigate the potential requirement for ligand bivalency in FcRn-mediated transport. The rFcRn-MDCK cells bind, internalize and bidirectionally transcytose the bivalent ligands IgG and Fc across polarized cell monolayers. However, they cannot be used to study FcRn-mediated transport of the monovalent ligand albumin, as we observe no specific binding, internalization or transcytosis of rat albumin. To address whether ligand bivalency is required for transport, the ability of rFcRn to transcytose and recycle wild-type Fc homodimers (wtFc; two FcRn-binding sites) and a heterodimeric Fc (hdFc; one FcRn-binding site) was compared. We show that ligand bivalency is not required for transcytosis or recycling, but that wtFc is transported more efficiently than hdFc, particularly at lower concentrations. We also demonstrate that hdFc and wtFc have different intracellular fates, with more hdFc than wtFc being trafficked to lysosomes and degraded, suggesting a role for avidity effects in FcRn-mediated IgG transport

A componential approach to individual differences in hypnotizability

Although responsiveness to hypnotic suggestions (hypnotizability) typically is conceptualized and studied as a singular homogeneous capability, numerous lines of evidence suggest instead that it is a hierarchically structured cognitive capacity comprising a core superordinate ability and ancillary subordinate component abilities. After reviewing current approaches to the measurement of hypnotizability and componential approaches to other cognitive capabilities, we highlight outstanding questions in the field and argue for a componential approach to the study of hypnotizability. Such an approach assumes that hypnotizability is not a unitary construct but is rooted in multiple subabilities that interact to give rise to individual differences that are expressed within specific contexts. We revisit previous componential work on hypnotizability and propose a series of steps by which a componential model can be more rigorously interrogated and integrated with contemporary advances in our understanding of human cognition

Beyond Strong Coupling in a Massively Multimode Cavity

The study of light-matter interaction has seen a resurgence in recent years, stimulated by highly controllable, precise, and modular experiments in cavity quantum electrodynamics (QED). The achievement of strong coupling, where the coupling between a single atom and fundamental cavity mode exceeds the decay rates, was a major milestone that opened the doors to a multitude of new investigations. Here we introduce multimode strong coupling (MMSC), where the coupling is comparable to the free spectral range (FSR) of the cavity, i.e. the rate at which a qubit can absorb a photon from the cavity is comparable to the round trip transit rate of a photon in the cavity. We realize, via the circuit QED architecture, the first experiment accessing the MMSC regime, and report remarkably widespread and structured resonance fluorescence, whose origin extends beyond cavity enhancement of sidebands. Our results capture complex multimode, multiphoton processes, and the emergence of ultranarrow linewidths. Beyond the novel phenomena presented here, MMSC opens a major new direction in the exploration of light-matter interactions.Comment: 14 pages, 11 figures. References added, typos correcte

Method and Meaning: Selections from the Gettysburg College Collection

What is art historical study and how it should be carried out are fundamental questions the exhibition Method and Meaning: Selections from the Gettysburg College Collection intends to answer. This student-curated exhibition is an exciting academic endeavor of seven students of art history majors and minors in the Art History Methods course. The seven student curators are Shannon Callahan, Ashlie Cantele, Maura D’Amico, Xiyang Duan, Devin Garnick, Allison Gross and Emily Zbehlik. As part of the class assignment, this exhibition allows the students to explore various art history methods on individual case studies. The selection of the works in the exhibition reflects a wide array of student research interests including an example of 18th century Chinese jade chime stone, jade and bronze replicas of ancient Chinese bronze vessels, a piece of early 20th century Chinese porcelain, oil paintings by Pennsylvania Impressionist painter Fern Coppedge, prints by Salvador Dalí and by German artist Käthe Kollwitz, and an early 20th century wood block print by Japanese artist Kawase Hasui. [excerpt]https://cupola.gettysburg.edu/artcatalogs/1014/thumbnail.jp

Transcriptome profiling of Set5 and Set1 methyltransferases: Tools for visualization of gene expression

AbstractCells regulate transcription by coordinating the activities of multiple histone modifying complexes. We recently identified the yeast histone H4 methyltransferase Set5 and discovered functional overlap with the histone H3 methyltransferase Set1 in gene expression. Specifically, using next-generation RNA sequencing (RNA-Seq), we found that Set5 and Set1 function synergistically to regulate specific transcriptional programs at subtelomeres and transposable elements. Here we provide a comprehensive description of the methodology and analysis tools corresponding to the data deposited in NCBI's Gene Expression Omnibus (GEO) under the accession number GSE52086. This data complements the experimental methods described in Mas Martín G et al. (2014) and provides the means to explore the cooperative functions of histone H3 and H4 methyltransferases in the regulation of transcription. Furthermore, a fully annotated R code is included to enable researchers to use the following computational tools: comparison of significant differential expression (SDE) profiles; gene ontology enrichment of SDE; and enrichment of SDE relative to chromosomal features, such as centromeres, telomeres, and transposable elements. Overall, we present a bioinformatics platform that can be generally implemented for similar analyses with different datasets and in different organisms

Safety and effectiveness of acetadote for acetaminophen toxicity.

BACKGROUND: Acetaminophen (APAP) toxicity is commonly encountered in the Emergency Department. Until 2004, treatment consisted of either oral N-acetylcysteine (NAC) or filtered oral NAC administered intravenously (i.v.). Intravenous acetylcysteine (Acetadote) is a new Food and Drug Administration-approved i.v. formulation of acetylcysteine manufactured by Cumberland Pharmaceuticals in Nashville, Tennessee. Little post-marketing data exists on the effectiveness and safety of i.v. acetylcysteine. OBJECTIVES: We evaluated the clinical presentations and outcomes of patients treated with i.v. acetylcysteine for APAP toxicity. METHODS: We performed a retrospective chart review of patients treated with i.v. acetylcysteine for APAP ingestion. The primary outcome measures were: adverse reactions to and effectiveness of i.v. acetylcysteine, as defined by elevation of transaminases, liver failure, renal failure, death, and hospital length of stay (LOS). Data collected included: comorbidities, allergies, intentionality, timing and dosing of i.v. acetylcysteine, hospital LOS, transaminases \u3e 1000 IU/L, development of liver failure requiring transplant, development of renal failure requiring hemodialysis, death, and anaphylactoid reactions. RESULTS: Sixty-four patients met our study criteria. Overall, 16 (25%) patients developed transaminases \u3e 1000 IU/L, 4 (6%) of them died and 2 (3%) received liver transplants. Of the 15 patients (23%) treated within 8 h, none died or developed liver or renal failure, and only 1 developed transient transaminase elevation \u3e 1000 IU/L. In the patients treated outside of 8 h, the median LOS was 3 days, whereas the group treated within 8 h had a median LOS of only 1 day. Six (9%) patients developed anaphylactoid reactions, 2 of whom received the i.v. acetylcysteine bolus over 15 min. Five of these patients were treated pharmacologically and completed treatment, and one had treatment discontinued for undocumented reasons. CONCLUSION: Intravenous acetylcysteine seemed to be a safe and effective formulation of N-acetylcysteine

Activation of optimally and unfavourably oriented faults in a uniform local stress field during the 2011 Prague, Oklahoma, sequence

The orientations of faults activated relative to the local principal stress directions can provide insights into the role of pore pressure changes in induced earthquake sequences. Here, we examine the 2011 M 5.7 Prague earthquake sequence that was induced by nearby wastewater disposal. We estimate the local principal compressive stress direction near the rupture as inferred from shear wave splitting measurements at spatial resolutions as small as 750 m. We find that the dominant azimuth observed is parallel to previous estimates of the regional compressive stress with some secondary azimuths oriented subparallel to the strike of the major fault structures. From an extended catalogue, we map ten distinct fault segments activated during the sequence that exhibit a wide array of orientations. We assess whether the five near-vertical fault planes are optimally oriented to fail in the determined stress field. We find that only two of the fault planes, including the M   5.7 main shock fault, are optimally oriented. Both the M 4.8 foreshock and M   4.8 aftershock occur on fault planes that deviate 20–29° from the optimal orientation for slip. Our results confirm that induced event sequences can occur on faults not optimally oriented for failure in the local stress field. The results suggest elevated pore fluid pressures likely induced failure along several of the faults activated in the 2011 Prague sequence

Regional Climate Trends and Scenarios for the U.S. National Climate Assessment Part 4. Climate of the U.S. Great Plains

This document is one of series of regional climate descriptions designed to provide input that can be used in the development of the National Climate Assessment (NCA). As part of a sustained assessment approach, it is intended that these documents will be updated as new and well-vetted model results are available and as new climate scenario needs become clear. It is also hoped that these documents (and associated data and resources) are of direct benefit to decision makers and communities seeking to use this information in developing adaptation plans. There are nine reports in this series, one each for eight regions defined by the NCA, and one for the contiguous U.S. The eight NCA regions are the Northeast, Southeast, Midwest, Great Plains, Northwest, Southwest, Alaska, and Hawai‘i/Pacific Islands. These documents include a description of the observed historical climate conditions for each region and a set of climate scenarios as plausible futures – these components are described in more detail below. While the datasets and simulations in these regional climate documents are not, by themselves, new, (they have been previously published in various sources), these documents represent a more complete and targeted synthesis of historical and plausible future climate conditions around the specific regions of the NCA. There are two components of these descriptions. One component is a description of the historical climate conditions in the region. The other component is a description of the climate conditions associated with two future pathways of greenhouse gas emissions

Comparison of FcRn- and pIgR-Mediated Transport in MDCK Cells by Fluorescence Confocal Microscopy

Protein delivery across polarized epithelia is controlled by receptor-mediated transcytosis. Many studies have examined basolateral-to-apical trafficking of polymeric IgA (pIgA) by the polymeric immunoglobulin receptor (pIgR). Less is known about apical-to-basolateral transcytosis, the direction the neonatal Fc receptor (FcRn) transports maternal IgGs across intestinal epithelia. To compare apical-to-basolateral and basolateral-to-apical transcytosis, we co-expressed FcRn and pIgR in Madin-Darby canine kidney (MDCK) cells and used pulse-chase experiments with confocal microscopy to examine transport of apically applied IgG Fcγ and basolaterally applied pIgA. Fcγ and pIgA trafficking routes were initially separate but intermixed at later chase times. Fcγ was first localized near the apical surface, but became more equally distributed across the cell, consistent with concomitant transcytosis and recycling. By contrast, pIgA transport was strongly unidirectional: pIgA shifted from near the basolateral surface to an apical location with increasing time. Some Fcγ and pIgA fluorescence colocalized in early (EEA1-positive), recycling (Rab11a-positive), and transferrin (Tf)-positive common/basolateral recycling endosomes. Fcγ became more enriched in Tf-positive endosomes with time, whereas pIgA was sorted from these compartments. Live-cell imaging revealed that vesicles containing Fcγ or pIgA shared similar mobility characteristics and were equivalently affected by depolymerizing microtubules, indicating that both trafficking routes depended to roughly the same extent on intact microtubules