Biophysical and Functional Characterization of Rhesus Macaque IgG Subclasses

Antibodies raised in Indian rhesus macaques [Macaca mulatta (MM)] in many preclinical vaccine studies are often evaluated in vitro for titer, antigen-recognition breadth, neutralization potency, and/or effector function, and in vivo for potential associations with protection. However, despite reliance on this key animal model in translation of promising candidate vaccines for evaluation in first in man studies, little is known about the properties of MM immunoglobulin G (IgG) subclasses and how they may compare to human IgG subclasses. Here, we evaluate the binding of MM IgG1, IgG2, IgG3, and IgG4 to human Fc gamma receptors (FcgammaR) and their ability to elicit the effector functions of human FcgammaR-bearing cells, and unlike in humans, find a notable absence of subclasses with dramatically silent Fc regions. Biophysical, in vitro, and in vivo characterization revealed MM IgG1 exhibited the greatest effector function activity followed by IgG2 and then IgG3/4. These findings in rhesus are in contrast with the canonical understanding that IgG1 and IgG3 dominate effector function in humans, indicating that subclass-switching profiles observed in rhesus studies may not strictly recapitulate those observed in human vaccine studies

Comparisons of Limb Structural Properties in Free-Ranging Chimpanzees From Kibale, Gombe, Mahale and Taï Communities

Structural characteristics of limbs bones provide insight into how an animal dynamically loads its limbs during life. Cause-and-effect relationships between loading and the osteogenic response it elicits are complex. In spite of such complexities, cross-sectional geometric properties can be useful indicators of locomotor repertoires. Typical comparisons use primates that are distinguished by broad habitual locomotor differences, usually with samples garnered from several museum collections. Intraspecific variability is difficult to investigate in such samples because behavior or life histories, which are tools for interpreting intraspecific variability, are limited. Clearly intraspecific variation both in morphology and behavior/life history exists. Here we expand an ongoing effort towards understanding intraspecific variation in limb structural properties by comparing free-ranging chimpanzees that have associated behavioral and life history data. Humeral and femoral data from eleven adult chimpanzees (Pan troglodytes) of Kibale National Park (Uganda) are compared to 29 adult habituated chimpanzees from Gombe (Tanzania), Mahale Mountains (Tanzania), and Taï Forest (Côte d’Ivoire) National Park communities. Overall, limb structural morphology of Kibale chimpanzees most resembles limb structural morphology of Mahale chimpanzees. Shape ratios and percentage cortical areas of Kibale chimpanzees are most similar to non-Gombe chimpanzees, while Kibale structural properties (e.g., maximum rigidity) are most similar to non-Taï structural properties. Even after adding Kibale females, Taï females continue to stand out from females in other communities. This research was supported in part by the L.S.B. Leakey Foundation and the National Science Foundation (DDIG, BCS-0002686).Human Evolutionary Biolog

A Phase-Field Model of Spiral Dendritic Growth

Domains of condensed-phase monolayers of chiral molecules exhibit a variety of interesting nonequilibrium structures when formed via pressurization. To model these domain patterns, we add a complex field describing the tilt degree of freedom to an (anisotropic) complex-phase-field solidification model. The resulting formalism allows for the inclusion of (in general, non-reflection symmetric) interactions between the tilt, the solid-liquid interface, and the bond orientation. Simulations demonstrate the ability of the model to exhibit spiral dendritic growth.Comment: text plus Four postscript figure file

Interplay of disorder and nonlinearity in Klein-Gordon models: Immobile kinks

We consider Klein-Gordon models with a $\delta$-correlated spatial disorder. We show that the properties of immobile kinks exhibit strong dependence on the assumptions as to their statistical distribution over the minima of the effective random potential. Namely, there exists a crossover from monotonically increasing (when a kink occupies the deepest potential well) to the non-monotonic (at equiprobable distribution of kinks over the potential minima) dependence of the average kink width as a function of the disorder intensity. We show also that the same crossover may take place with changing size of the system.Comment: 7 pages, 4 figure

Resonant steps and spatiotemporal dynamics in the damped dc-driven Frenkel-Kontorova chain

Kink dynamics of the damped Frenkel-Kontorova (discrete sine-Gordon) chain driven by a constant external force are investigated. Resonant steplike transitions of the average velocity occur due to the competitions between the moving kinks and their radiated phasonlike modes. A mean-field consideration is introduced to give a precise prediction of the resonant steps. Slip-stick motion and spatiotemporal dynamics on those resonant steps are discussed. Our results can be applied to studies of the fluxon dynamics of 1D Josephson-junction arrays and ladders, dislocations, tribology and other fields.Comment: 20 Plain Latex pages, 10 Eps figures, to appear in Phys. Rev.

On the existence of internal modes of sine-Gordon kinks

We study whether or not sine-Gordon kinks exhibit internal modes or ``quasimodes.'' By considering the response of the kinks to ac forces and initial distortions, we show that neither intrinsic internal modes nor ``quasimodes'' exist in contrast to previous reports. However, we do identify a different kind of internal mode bifurcating from the bottom edge of the phonon band which arises from the discretization of the system in the numerical simulations, thus confirming recent predictions.Comment: 4 pages, 2 figures, REVTeX, to appear as a Rapid Communication in Phys Rev E (July 1st

Why are animals cognitive?

The study of animal behaviour has revealed many intricate ways in which individuals deal adaptively with their world, some of which raise controversial issues of interpretation. Scrub jays, for instance, adjust their food-hiding according to the likely competition from other jays. If a competitor has seen them cache food, and they have themselves had the experience of pilfering others ’ caches, they re-cache in private [1]. If privacy is denied them, they prefer t

Safety and Efficacy of Omaveloxolone in Friedreich Ataxia (MOXIe Study)

OBJECTIVE: Friedreich's ataxia (FRDA) is a progressive genetic neurodegenerative disorder with no approved treatment. Omaveloxolone, an Nrf2 activator, improves mitochondrial function, restores redox balance, and reduces inflammation in models of FRDA. We investigated the safety and efficacy of omaveloxolone in patients with FRDA. METHODS: We conducted an international, double-blind, randomized, placebo-controlled parallel-group, registrational phase 2 trial at 11 institutions in the United States, Europe, and Australia (NCT02255435, EudraCT2015-002762-23). Eligible patients, 16 to 40 years of age with genetically confirmed FRDA and baseline modified Friedreich's Ataxia Rating Scale (mFARS) scores between 20 and 80, were randomized 1:1 to placebo or 150 mg per day of omaveloxolone. The primary outcome was change from baseline in the mFARS score in those treated with omaveloxolone compared with those on placebo at 48 weeks. RESULTS: 155 patients were screened and 103 were randomly assigned to receive omaveloxolone (n=51) or placebo (n=52), with 40 omaveloxolone patients and 42 placebo patients analyzed in the full analysis set. Changes from baseline in mFARS scores in omaveloxolone (-1.55 ± 0.69) and placebo (0.85 ± 0.64) patients showed a difference between treatment groups of -2.40 ± 0.96; p=0.014). Transient reversible increases in aminotransferase levels were observed with omaveloxolone without increases in total bilirubin or other signs of liver injury. Headache, nausea, and fatigue were also more common among patients receiving omaveloxolone. INTERPRETATION: In the MOXIe trial, omaveloxolone significantly improved neurological function compared to placebo and was generally safe and well tolerated. It represents a potential therapeutic agent in FRDA. This article is protected by copyright. All rights reserved

Biophysical and Functional Characterization of Rhesus Macaque IgG Subclasses

Antibodies raised in Indian rhesus macaques [Macaca mulatta (MM)] in many preclinical vaccine studies are often evaluated in vitro for titer, antigen-recognition breadth, neu- tralization potency, and/or effector function, and in vivo for potential associations with protection. However, despite reliance on this key animal model in translation of promising candidate vaccines for evaluation in first in man studies, little is known about the proper- ties of MM immunoglobulin G (IgG) subclasses and how they may compare to human IgG subclasses. Here, we evaluate the binding of MM IgG1, IgG2, IgG3, and IgG4 to human Fc gamma receptors (FcγR) and their ability to elicit the effector functions of human FcγR-bearing cells, and unlike in humans, find a notable absence of subclasses with dramatically silent Fc regions. Biophysical, in vitro, and in vivo characterization revealed MM IgG1 exhibited the greatest effector function activity followed by IgG2 and then IgG3/4. These findings in rhesus are in contrast with the canonical understanding that IgG1 and IgG3 dominate effector function in humans, indicating that subclass-switching profiles observed in rhesus studies may not strictly recapitulate those observed in human vaccine studies