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MSTPublications: December 2020

Posted by on Friday, December 18, 2020 in New Publications .

Diflunisal-loaded poly(propylene sulfide) nanoparticles decrease S. aureus-mediated bone destruction during osteomyelitis.
Ford CA, Spoonmore TJ, Gupta MK, Duvall CL, Guelcher SA, Cassat JE.
J Orthop Res. 2020 Dec 10. doi: 10.1002/jor.24948. Online ahead of print.

Osteomyelitis is a debilitating infection of bone that results in substantial morbidity. Staphylococcus aureus is the most commonly isolated pathogen causing bone infections and features an arsenal of virulence factors that contribute to bone destruction and counteract immune responses. We previously demonstrated that diflunisal, a non‐steroidal anti‐inflammatory drug (NSAID), decreases S. aureus‐induced bone destruction during osteomyelitis when delivered locally from a resorbable drug delivery depot. However, local diflunisal therapy was complicated by bacterial colonization of the depot’s surface, highlighting a common pitfall of devices for local drug delivery to infected tissue. It is therefore critical to develop an alternative drug delivery method for diflunisal to successfully repurpose this drug as an antivirulence therapy for osteomyelitis. We hypothesized that a nanoparticle‐based parenteral delivery strategy would provide a method for delivering diflunisal to infected tissue while circumventing the complications associated with local delivery. In this work, we demonstrate that poly(propylene sulfide) (PPS) nanoparticles accumulate at the infectious focus in a murine model of staphylococcal osteomyelitis and are capable of efficaciously delivering diflunisal to infected bone. Moreover, diflunisal‐loaded PPS nanoparticles effectively decrease S. aureus‐mediated bone destruction, establishing the feasibility of systemic delivery of an antivirulence compound to mitigate bone pathology during osteomyelitis.

Stimulus Feature-Specific Information Flow Along the Columnar Cortical Microcircuit Revealed by Multivariate Laminar Spiking Analysis.
Tovar DA, Westerberg JA, Cox MA, Dougherty K, Carlson TA, Wallace MT, Maier A.
Front Syst Neurosci. 2020 Nov 30;14:600601. doi: 10.3389/fnsys.2020.600601. eCollection 2020.

Most of the mammalian neocortex is comprised of a highly similar anatomical structure, consisting of a granular cell layer between superficial and deep layers. Even so, different cortical areas process different information. Taken together, this suggests that cortex features a canonical functional microcircuit that supports region-specific information processing. For example, the primate primary visual cortex (V1) combines the two eyes’ signals, extracts stimulus orientation, and integrates contextual information such as visual stimulation history. These processes co-occur during the same laminar stimulation sequence that is triggered by the onset of visual stimuli. Yet, we still know little regarding the laminar processing differences that are specific to each of these types of stimulus information. Univariate analysis techniques have provided great insight by examining one electrode at a time or by studying average responses across multiple electrodes. Here we focus on multivariate statistics to examine response patterns across electrodes instead. Specifically, we applied multivariate pattern analysis (MVPA) to linear multielectrode array recordings of laminar spiking responses to decode information regarding the eye-of-origin, stimulus orientation, and stimulus repetition. MVPA differs from conventional univariate approaches in that it examines patterns of neural activity across simultaneously recorded electrode sites. We were curious whether this added dimensionality could reveal neural processes on the population level that are challenging to detect when measuring brain activity without the context of neighboring recording sites. We found that eye-of-origin information was decodable for the entire duration of stimulus presentation, but diminished in the deepest layers of V1. Conversely, orientation information was transient and equally pronounced along all layers. More importantly, using time-resolved MVPA, we were able to evaluate laminar response properties beyond those yielded by univariate analyses. Specifically, we performed a time generalization analysis by training a classifier at one point of the neural response and testing its performance throughout the remaining period of stimulation. Using this technique, we demonstrate repeating (reverberating) patterns of neural activity that have not previously been observed using standard univariate approaches.

Cortical Auditory Processing of Simple Stimuli Is Altered in Autism: A Meta-analysis of Auditory Evoked Responses.
Williams ZJ, Abdelmessih PG, Key AP, Woynaroski TG.
Biol Psychiatry Cogn Neurosci Neuroimaging. 2020 Sep 22:S2451-9022(20)30280-9. doi: 10.1016/j.bpsc.2020.09.011. Online ahead of print.

Background: Auditory perceptual abnormalities are common in persons on the autism spectrum. The neurophysiologic underpinnings of these differences have frequently been studied using auditory event-related potentials (ERPs) and event-related magnetic fields (ERFs). However, no study to date has quantitatively synthesized this literature to determine whether early auditory ERP/ERF latencies or amplitudes in autistic persons differ from those of typically developing control subjects.
Methods: We searched PubMed and ProQuest for studies comparing 1) latencies/amplitudes of P1/M50, N1b, N1c, M100, P2/M200, and/or N2 ERP/ERF components evoked by pure tones and 2) paired-click sensory gating (P1/N1b amplitude suppression) in autistic individuals and typically developing control subjects. Effects were synthesized using Bayesian 3-level meta-analysis.
Results: In response to pure tones, autistic individuals exhibited prolonged P1/M50 latencies (g = 0.341 [95% credible interval = 0.166, 0.546]), prolonged M100 latencies (g = 0.319 [0.093, 0.550]), reduced N1c amplitudes (g = -0.812 [-1.278, -0.187]), and reduced N2 amplitudes (g = -0.374 [-0.633, -0.179]). There were no practically significant group differences in P2/M200 latencies, N2 latencies, P1/M50 amplitudes, N1b amplitudes, M100 amplitudes, or P2/M200 amplitudes. Paired-click sensory gating was also reduced in autistic individuals (g = -0.389 [-0.619, -0.112]), although this effect was primarily driven by smaller responses to the first click stimulus.
Conclusions: Relative to typically developing control subjects, autistic individuals demonstrate multiple alterations in early cortical auditory processing of simple stimuli. However, most group differences were modest in size and based on small numbers of heterogeneous studies with variable quality. Future work is necessary to understand whether these neurophysiologic measures can predict clinically meaningful outcomes or serve as stratification biomarkers for the autistic population.

A genetic mouse model recapitulates immune checkpoint inhibitor-associated myocarditis and supports a mechanism-based therapeutic intervention.
Wei SC, Meijers WC, Axelrod ML, Anang NAS, Screever EM, Wescott EC, Johnson DB, Whitley E, Lehmann L, Courand PY, Mancuso JJ, Himmel LE, Lebrun-Vignes B, Wleklinski MJ, Knollmann BC, Srinivasan J, Li Y, Atolagbe OT, Rao X, Zhao Y, Wang J, Ehrlich LIR, Sharma P, Salem JE, Balko JM, Moslehi JJ, Allison JP.
Cancer Discov. 2020 Nov 30:CD-20-0856. doi: 10.1158/2159-8290.CD-20-0856. Online ahead of print.

Impact of implantation time on early function of cardiac transplant.
Kuzemchak MD, Foley NM, Colazo JM, Rahaman ZM, Danter MR, Balsara KR, Schlendorf KH, Shah AS.
J Card Surg. 2020 Dec 1. doi: 10.1111/jocs.15214. Online ahead of print.

Glutathione reductase deficiency alters lung development and hyperoxic responses in neonatal mice.
Robbins ME, Cho HY, Hansen JM, Luchsinger JR, Locy ML, Velten M, Kleeberger SR, Rogers LK, Tipple TE.
Redox Biol. 2020 Nov 13;38:101797. doi: 10.1016/j.redox.2020.101797. Online ahead of print.

Lower Cardiac Output Relates to Longitudinal Cognitive Decline in Aging Adults.
Bown CW, Do R, Khan OA, Liu D, Cambronero FE, Moore EE, Osborn KE, Gupta DK, Pechman KR, Mendes LA, Hohman TJ, Gifford KA, Jefferson AL.
Front Psychol. 2020 Nov 9;11:569355. doi: 10.3389/fpsyg.2020.569355. eCollection 2020.

Genetic ablation of serotonin receptor 2B improves aortic valve hemodynamics of Notch1 heterozygous mice in a high-cholesterol diet model.
Joll JE 2nd, Clark CR, Peters CS, Raddatz MA, Bersi MR, Merryman WD.
PLoS One. 2020 Nov 25;15(11):e0238407. doi: 10.1371/journal.pone.0238407. eCollection 2020.

Increased pain sensitivity and pain-related anxiety in individuals with autism.
Failla MD, Gerdes MB, Williams ZJ, Moore DJ, Cascio CJ.
Pain Rep. 2020 Nov 16;5(6):e861. doi: 10.1097/PR9.0000000000000861. eCollection 2020 Nov-Dec.

A Review of Decreased Sound Tolerance in Autism: Definitions, Phenomenology, and Potential Mechanisms.
Williams ZJ, He JL, Cascio CJ, Woynaroski TG.
Neurosci Biobehav Rev. 2020 Dec 4:S0149-7634(20)30672-2. doi: 10.1016/j.neubiorev.2020.11.030. Online ahead of print.