Antibody interactions with the capsular polysaccharide of Burkholderia pseudomallei

Burkholderia pseudomallei is an important human pathogen that causes melioidosis. Infection is highly lethal and notoriously difficult to diagnose and treat. As such, it has tremendous bioterror potential and has been classified as a Tier 1 select agent by the Centers for Disease Control and the Department of Health & Human Services. One reason that B. pseudomallei is a successful pathogen is that it is surrounded by a high molecular weight capsular polysaccharide (CPS) comprised of mannoheptopyranose residues. CPS inhibits complement deposition, prevents phagocytosis, and greatly enhances virulence. Previous studies have indicated that antibodies targeting CPS have high therapeutic value and can be used to diagnose B. pseudomallei infection. The present work describes the development and characterization of 15 monoclonal antibodies (mAbs) in an effort to further the understanding of how antibodies interact with B. pseudomallei CPS. We have generated two complete Immunoglobulin G (IgG) subclass families; subclass families are antibodies that have identical variable regions, but different constant regions, and thus different effector functions. We have determined that some of these mAbs are protective in a murine model of pulmonary melioidosis in a subclass-independent manner. In this study, protection appears to be a function of mAb binding affinity. Additionally, we determined that non-IgG3 mAbs are best for diagnosing active infection. Isolating a high affinity IgG3 and generating a subclass-switch family yielded mAbs with low affinities that did not perform well in a diagnostic test format. Thus, immunization strategies should focus on eliciting alternative IgG immune responses. Using this information, we have updated a prototype Active Melioidosis Detect™ Lateral Flow Immunoassay (AMD LFI) by replacing the original IgG3 mAb with a high affinity IgG1 mAb. This updated AMD LFI has increased sensitivity, is highly specific, and rapid; it can detect B. pseudomallei CPS in multiple sample types in 15 minutes or less

Magnetic Resonance Relaxation Anisotropy:Physical Principles and Uses in Microstructure Imaging

Magnetic resonance imaging (MRI) provides an excellent means of studying tissue microstructure noninvasively since the microscopic tissue environment is imprinted on the MRI signal even at macroscopic voxel level. Mesoscopic variations in magnetic field, created by microstructure, influence the transverse relaxation time (T(2)) in an orientation-dependent fashion (T(2) is anisotropic). However, predicting the effects of microstructure upon MRI observables is challenging and requires theoretical insight. We provide a formalism for calculating the effects upon T(2) of tissue microstructure, using a model of cylindrical magnetic field perturbers. In a cohort of clinically healthy adults, we show that the angular information in spin-echo T(2) is consistent with this model. We show that T(2) in brain white matter of nondemented volunteers follows a U-shaped trajectory with age, passing its minimum at an age of ∼30 but that this depends on the particular white matter tract. The anisotropy of T(2) also interacts with age and declines with increasing age. Late-myelinating white matter is more susceptible to age-related change than early-myelinating white matter, consistent with the retrogenesis hypothesis. T(2) mapping may therefore be incorporated into microstructural imaging

Forward and Inverse Modeling of the Emission and Transmission Spectrum of GJ 436b: Investigating Metal Enrichment, Tidal Heating, and Clouds

The Neptune-mass GJ 436b is one of the most-studied transiting exoplanets with repeated measurements of both its thermal emission and transmission spectra. We build on previous studies to answer outstanding questions about this planet, including its potentially high metallicity and tidal heating of its interior. We present new observations of GJ 436b's thermal emission at 3.6 and 4.5 micron, which reduce uncertainties in estimates of GJ 436b's flux at those wavelengths and demonstrate consistency between Spitzer observations spanning more than 7 years. We analyze the Spitzer thermal emission photometry and Hubble WFC3 transmission spectrum in tandem. We use a powerful dual-pronged modeling approach, comparing these data to both self-consistent and retrieval models. We vary the metallicity, intrinsic luminosity from tidal heating, disequilibrium chemistry, and heat redistribution. We also study the effect of clouds and photochemical hazes on the spectra, but do not find strong evidence for either. The self-consistent and retrieval modeling combine to suggest that GJ 436b has a high atmospheric metallicity, with best fits at or above several hundred times solar metallicity, tidal heating warming its interior with best-fit intrinsic effective effective temperatures around 300--350 K, and disequilibrium chemistry. High metal-enrichments (>600x solar) can only occur from the accretion of rocky, rather than icy, material. Assuming Tint~300--350 K, we find that Q'~2x10^5--10^6, larger than Neptune's Q', and implying a long tidal circularization timescale for the planet's orbit. We suggest that Neptune-mass planets may be a more diverse class than previously imagined, with metal-enhancements potentially spanning several orders of magnitude, to perhaps over 1000x solar metallicity. High fidelity observations with instruments like JWST will be critical for characterizing this diversity.Comment: 15 pages, 18 figures. Revised for publication in Ap

Rituximab : a novel treatment for Pemphigus in Malta

Until recently, the main treatment for pemphigus has been systemic corticosteroids, usually administered at high doses with consequent side-effects. Lately, the biological agent rituximab has been introduced as an effective treatment for this condition. This article describes seven cases of pemphigus successfully treated with rituximab in Malta and discusses the benefits and drawbacks of this novel treatment modality.peer-reviewe

Targeting tobacco in a community-based addiction recovery cohort: Results from a computerized, brief, randomized intervention trial

Introduction. Nearly 80% of substance dependent individuals also use tobacco, and smoking cessation efforts during treatment for other substance use is associated with similar or even improved outcomes. However, smoking cessation is not routinely addressed during treatment for substance use disorders. The present study tested a computerized brief motivational intervention (C-BMI) for smoking cessation in an understudied population: a cohort recruited from a recovery community organization (RCO) center. Methods. Following baseline assessment, participants were randomly assigned to either a 30-minute C-BMI plus access to free nicotine replacement therapy (NRT), or an information-only control group plus NRT access. Results. Reductions in CO were observed for both groups. Quit rates in the C-BMI group (5%-7%, vs. 0% for the control group) approximated those observed elsewhere for physician advice and minimal counseling. Participants in the C-BMI group were also more likely to express a desire to quit. Conclusions. Computer-delivered smoking cessation interventions within RCOs appear feasible. These organizations treat a wide variety of individuals, and C-BMIs for smoking in this context have the potential to reduce smoking-related morbidity and mortality

Plasma catecholamines and social behavior in male vervet monkeys (Cercopithecus aethiops sabaeus)

Many investigations in humans indicate that epinephrine, norepinephrine and their ratio may correlate with such traits as social competence, academic achievement, and aggression. However, the socioeconomic, dietary, and environmental confounds accompanying most human studies complicate their interpretation. Social status, aggression, and other social behaviors can be reliably assessed in nonhuman primates under conditions controlling for crucial environmental factors. If interpretation of human studies is correct, dominant and subordinate male vervet monkeys should exhibit distinctive patterns of catecholamine secretion. To test this possibility, seventeen adult male monkeys living in six stable social groups were observed for 6 months. Based on their success in agonistic events, subjects were categorized as dominant or subordinate. Alpha scores were calculated from empirically derived factors to provide a noncategorical measure of dominant behavioral style. Plasma epinephrine and norepinephrine samples obtained from anesthetized subjects did not differ between dominant and subordinate males. Alpha scores, however, distinguished high from low norepinephrine/epinephrine ratio groups. These findings are consistent with studies in humans linking high epinephrine, low norepinephrine, and social competence.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30093/1/0000465.pd