Faculty Bibliography

BACKGROUND:Bringing antibodies from pre-clinical studies to human trials requires humanization, but this process may alter properties that are crucial for efficacy. Since pathological tau protein is primarily intraneuronal in Alzheimer's disease, the most efficacious antibodies should work both intra- and extracellularly. Thus, changes which impact uptake or antibody binding will affect antibody efficacy. METHODS:Initially, we examined four tau mouse monoclonal antibodies with naturally differing charges. We quantified their neuronal uptake, and efficacy in preventing toxicity and pathological seeding induced by human-derived pathological tau. Later, we generated a human chimeric 4E6 (h4E6), an antibody with well documented efficacy in multiple tauopathy models. We compared the uptake and efficacy of unmodified and chimeric antibodies in neuronal and differentiated neuroblastoma cultures. Further, we analyzed tau binding using ELISA assays. FINDINGS/RESULTS:Neuronal uptake of tau antibodies and their efficacy strongly depends on antibody charge. Additionally, their ability to prevent tau toxicity and seeding of tau pathology does not necessarily go together. Particularly, chimerization of 4E6 increased its charge from 6.5 to 9.6, which blocked its uptake into human and mouse cells. Furthermore, h4E6 had altered binding characteristics despite intact binding sites, compared to the mouse antibody. Importantly, these changes in uptake and binding substantially decreased its efficacy in preventing tau toxicity, although under certain conditions it did prevent pathological seeding of tau. CONCLUSIONS:These results indicate that efficacy of chimeric/humanized tau antibodies should be thoroughly characterized prior to clinical trials, which may require further engineering to maintain or improve their therapeutic potential. FUND: National Institutes of Health (NS077239, AG032611, R24OD18340, R24OD018339 and RR027990, Alzheimer's Association (2016-NIRG-397228) and Blas Frangione Foundation.

In the olfactory system, odor percepts retain their identity despite substantial variations in concentration, timing, and background. We study a novel strategy for encoding intensity-invariant stimulus identity that is based on representing relative rather than absolute values of stimulus features. For example, in what is known as the primacy coding model, odorant identities are represented by the conditions that some odorant receptors are activated more strongly than others. Because, in this scheme, odorant identity depends only on the relative amplitudes of olfactory receptor responses, identity is invariant to changes in both intensity and monotonic nonlinear transformations of its neuronal responses. Here we show that sparse vectors representing odorant mixtures can be recovered in a compressed sensing framework via elastic net loss minimization. In the primacy model, this minimization is performed under the constraint that some receptors respond to a given odorant more strongly than others. Using duality transformation, we show that this constrained optimization problem can be solved by a neural network whose Lyapunov function represents the dual Lagrangian and whose neural responses represent the Lagrange coefficients of primacy and other constraints. The connectivity in such a dual network resembles known features of connectivity in olfactory circuits. We thus propose that networks in the piriform cortex implement dual computations to compute odorant identity with the sparse activities of individual neurons representing Lagrange coefficients. More generally, we propose that sparse neuronal firing rates may represent Lagrange multipliers, which we call the dual brain hypothesis. We show such a formulation is well suited to solve problems with multiple interacting relative constraints.

OBJECTIVE:The orofacial primary motor cortex (MIo) plays a critical role in controlling tongue and jaw movements during oral motor functions, such as chewing, swallowing and speech. However, the neural mechanisms of MIo during naturalistic feeding are still poorly understood. There is a strong need for a systematic study of motor cortical dynamics during feeding behavior. APPROACH/METHODS:To investigate the neural dynamics and variability of MIo neuronal activity during naturalistic feeding, we used chronically implanted micro-electrode arrays to simultaneously recorded ensembles of neuronal activity in MIo of two monkeys (Macaca mulatta) while eating various types of food. We developed a Bayesian nonparametric latent variable model to reveal latent structures of neuronal population activity of MIo and identify the complex mapping between MIo ensemble spike activity and high-dimensional kinematics. MAIN RESULTS/RESULTS:Rhythmic neuronal firing patterns and oscillatory dynamics are evident in single-unit activity. At the population level, we uncovered the neural dynamics of rhythmic chewing, and quantified the neural variability at multiple timescales (complete feeding sequences, chewing sequence stages, chewing gape cycle phases) across food types. Our approach accommodates time-warping of chewing sequences and automatic model selection, and maps the latent states to chewing behaviors at fine timescales. SIGNIFICANCE/CONCLUSIONS:Our work shows that neural representations of MIo ensembles display spatiotemporal patterns in chewing gape cycles at different chew sequence stages, and these patterns vary in a stage-dependent manner. Unsupervised learning and decoding analysis may reveal the link between complex MIo spatiotemporal patterns and chewing kinematics.

Introduction: Short sleep duration promotes metabolic dysregulation and obesity. We have previously shown that acute sleep restriction increases neuronal activity in response to food stimuli in areas of interoception and reward, such as the insula and orbitofrontal cortex. However, whether chronic mild sleep restriction impacts food reward valuation in the brain remains unknown. In an ongoing study, we assess the effects of mild 6-week sleep restriction on intrinsic functional connectivity (iFC) across reward and interoception- related brain circuitry.
Method(s): To date, 16 adult men and women (age 29.0+/-5.3 years and BMI 26.9+/-2.6 kg/m²at study entry) took part in this randomized, crossover, outpatient trial of 2 phases: habitual sleep (HS; >=7 h/night) and sleep restriction (SR; -1.5 h/night relative to HS). All participants were screened with actigraphy over a two-week period to ensure adequate sleep duration of 7-9 h/night (average screening total sleep time: 7.65+/-0.58 h/night). Two resting-state (task-free) functional MRI scans (Siemens Skyra 3T, TR=2.5s, two 5-min runs) were collected during the final week of each phase. Here we report preliminary analyses using the Data Processing & Analysis of Brain Imaging V2.3-170105 toolbox with paired-sample t-tests across the whole brain.
Result(s): Average sleep duration in the HS phase was 7.55+/-0.55 h/ night vs. 6.10+/-0.49 h/night during SR (p<0.0001). Examining iFC of 17 previously studied regions-of-interest relevant to food valuation and interoception yielded two significant results after correction for Gaussian Random Field (p<0.001 at voxel level, cluster p<0.05). iFC was greater following SR than HS for (1) left inferior frontal gyrus with medial prefrontal cortex (mPFC); and (2) mPFC with bilateral superior temporal gyrus.
Conclusion(s): This study provides preliminary evidence of decreased segregation between a key anterior node of the default mode network (mPFC) and nodes of the salience and somatosensory (auditory) networks under prolonged mild SR. Such iFC changes, suggesting atypical network coupling, if confirmed in the completed sample, will be examined in the future in relation to key measures of metabolism and cardiovascular risks

PURPOSE/OBJECTIVE:The purpose of the study was to assess the differences in the concentration and function of urinary proteins between patients with cystine stones (CYS) and healthy controls (HC). We postulated that CYS and HC groups would demonstrate different proteomic profiles. METHODS:A pilot study was performed comparing urinary proteomes of 10 patients with CYS and 10 age- and gender-matched HC, using liquid chromatography-mass spectrometry. Proteins which met the selection criteria (i) ≥ 2 unique peptide identifications; (ii) ≥ twofold difference in protein abundance; and (iii) ≤ 0.05 p value for the Fisher's Exact Test were analyzed using Gene Ontology classifications. RESULTS:Of the 2097 proteins identified by proteomic analysis, 398 proteins were significantly different between CYS and HC. Of those, 191 were involved in transport processes and 61 in inflammatory responses. The majority were vesicle-mediated transport proteins (78.5%), and 1/3 of them were down-regulated; of those, 12 proteins were involved in endosomal transport (including 6 charged multivesicular body proteins (CHMP) and 3 vacuolar sorting-associated proteins) and 9 in transmembrane transport. Myosin-2 and two actin-related proteins were significantly up-regulated in the vesicle-mediated transport group. CONCLUSION/CONCLUSIONS:We provide proteomic evidence of impaired endocytosis, dysregulation of actin and myosin cytoskeleton, and inflammation in CYS. Endosomal transport proteins were down-regulated mainly through defective CHMP. These findings may contribute to further understanding of the pathogenesis of CYS, potentially affecting its management.

A Quick guide to singing mice.

Awareness of the human health impacts of exposure to air pollution is growing rapidly. For example, it has become evident that the adverse health effects of air pollution are more pronounced in disadvantaged populations. Policymakers in many jurisdictions have responded to this evidence by enacting initiatives that lead to lower concentrations of air pollutants, such as urban traffic restrictions. In this review, we focus on the interplay between advances in environmental exposure assessment and developments in policy. We highlight recent progress in the granular measurement of air pollutants and individual-level exposures, and how this has enabled focused local policy actions. Finally, we detail an illustrative study designed to link individual-level health-relevant exposures with economic, behavioral, biological, familial, and environmental variables.

Ion channels facilitate the movement of ions across the plasma and organellar membranes. A recent symposium brought together scientists who study ion channels and transporters in immune cells, which highlighted advances in this emerging field and served to chart new avenues for investigating the roles of ion channels in immunity.