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Electroporation Safety Factor Of 300 Nanosecond And 10 Millisecond Defibrillation In Langendorff-Perfused Rabbit Hearts, Johanna U. Neuber, Andrei G. Pakhomov, Christian W. Zemlin

Open Access Publications

AIMS: Recently, a new defibrillation modality using nanosecond pulses was shown to be effective at much lower energies than conventional 10 millisecond monophasic shocks in ex vivo experiments. Here we compare the safety factors of 300 nanosecond and 10 millisecond shocks to assess the safety of nanosecond defibrillation.

METHODS AND RESULTS: The safety factor, i.e. the ratio of median effective doses (ED50) for electroporative damage and defibrillation, was assessed for nanosecond and conventional (millisecond) defibrillation shocks in Langendorff-perfused New Zealand white rabbit hearts. In order to allow for multiple shock applications in a single heart, a pair of needle electrodes …

Isolation Of Reconstructed Functional Ribonucleoprotein Complexes Of Machupo Virus, Jesse D. Pyle, Sean P.J. Whelan

Open Access Publications

Arenaviruses initiate infection by delivering a transcriptionally competent ribonucleoprotein (RNP) complex into the cytosol of host cells. The arenavirus RNP consists of the large (L) RNA-dependent RNA polymerase (RdRP) bound to a nucleoprotein (NP)-encapsidated genomic RNA (viral RNA [vRNA]) template. During transcription and replication, L must transiently displace RNA-bound NP to allow for template access into the RdRP active site. Concomitant with RNA replication, new subunits of NP must be added to the nascent complementary RNAs (cRNA) as they emerge from the product exit channel of L. Interactions between L and NP thus play a central role in arenavirus gene …

Comprehensive Characterization Of 536 Patient-Derived Xenograft Models Prioritizes Candidates For Targeted Treatment, Hua Sun, Song Cao, R. Jay Mashl, Chia-Kuei Mo, Sherri R. Davies, Tina M. Primeau, Jeremy Hoog, Jacqueline L. Mudd, Matthew A. Wyczalkowski, Reyka G. Jayasinghe, Fernanda Martins Rodrigues, Nadezhda V. Terekhanova, Yize Li, Kian-Huat Lim, Andrea Wang-Gillam, Brian A. Van Tine, Cynthia X. Ma, Katherine C. Fuh, John F. Dipersio, Julie Belmar, Jason Held, Rose Tipton, Yige Wu, Lijun Yao, Daniel Cui Zhou, Feng Chen, Shunqiang Li, Ramaswamy Govindan, Li Ding, Michael C. Wendl, Rebecca Aft, Julie K. Schwarz, Jose P. Zevallos, Sidharth V. Puram, Jingqin Luo, Ryan C. Fields, Et Al

Open Access Publications

No abstract provided.

Zika Virus Infection Of Pregnant Ifnar1-/- Mice Triggers Strain-Specific Differences In Fetal Outcomes, Ellie K. Bohm, Jennifer T. Vangorder-Braid, Anna S. Jaeger, Ryan V. Moriarty, John J. Baczenas, Natalie C. Bennett, Shelby L. O'Connor, Michael K. Fritsch, Nicole A. Fuhler, Kevin K. Noguchi, Matthew T. Aliota

Open Access Publications

Zika virus (ZIKV) is a flavivirus that causes a constellation of adverse fetal outcomes collectively termed congenital Zika syndrome (CZS). However, not all pregnancies exposed to ZIKV result in an infant with apparent defects. During the 2015 to 2016 American outbreak of ZIKV, CZS rates varied by geographic location. The underlying mechanisms responsible for this heterogeneity in outcomes have not been well defined. Therefore, we sought to characterize and compare the pathogenic potential of multiple Asian-/American-lineage ZIKV strains in an established

Spontaneous Bacterial Peritonitis Caused By Bordetella Hinzii, Grace C. Wang, Miranda J. Wallace, Gayathri Krishnan, Patrick D. Olson, Abigail L. Carlson, Gautam Dantas, James M. Fleckenstein

Open Access Publications

Although Bordetella hinzii coccobacilli is most commonly identified in respiratory tracts of birds and rodents, this organism has occasionally been isolated in human infections. We describe a case of B. hinzii spontaneous bacterial peritonitis in Missouri, USA. Whole-genome sequencing of blood and peritoneal fluid isolates confirmed B. hinzii infection.

Lyve1+ Macrophages Of Murine Peritoneal Mesothelium Promote Omentum-Independent Ovarian Tumor Growth, Nan Zhang, Anastasiia Gainullina, Emma C. Erlich, Emily J. Onufer, Rafael S. Czepielewski, Beth A. Helmink, Brian T. Saunders, Jesse W. Williams, Bernd H. Zinselmeyer, Gwendalyn J. Randolph, Ki-Wook Kim, Et Al

Open Access Publications

Two resident macrophage subsets reside in peritoneal fluid. Macrophages also reside within mesothelial membranes lining the peritoneal cavity, but they remain poorly characterized. Here, we identified two macrophage populations (LYVE1hi MHC IIlo-hi CX3CR1gfplo/- and LYVE1lo/- MHC IIhi CX3CR1gfphi subsets) in the mesenteric and parietal mesothelial linings of the peritoneum. These macrophages resembled LYVE1+ macrophages within surface membranes of numerous organs. Fate-mapping approaches and analysis of newborn mice showed that LYVE1hi macrophages predominantly originated from embryonic-derived progenitors and were controlled by CSF1 made by Wt1+ stromal cells. Their gene expression profile closely overlapped with ovarian tumor-associated macrophages previously described in the …

Modeling Spinal Locomotor Circuits For Movements In Developing Zebrafish, Yann Roussel, Stephanie F. Gaudreau, Emily R. Kacer, Mohini Sengupta, Tuan V. Bui

Open Access Publications

Many spinal circuits dedicated to locomotor control have been identified in the developing zebrafish. How these circuits operate together to generate the various swimming movements during development remains to be clarified. In this study, we iteratively built models of developing zebrafish spinal circuits coupled to simplified musculoskeletal models that reproduce coiling and swimming movements. The neurons of the models were based upon morphologically or genetically identified populations in the developing zebrafish spinal cord. We simulated intact spinal circuits as well as circuits with silenced neurons or altered synaptic transmission to better understand the role of specific spinal neurons. Analysis of …

Analysis Of Amyloid-Like Secondary Structure In The Cryab-R120g Knock-In Mouse Model Of Hereditary Cataracts By Two-Dimensional Infrared Spectroscopy, Ariel M. Alperstein, Kathleen S. Molnar, Sidney S. Dicke, Kieran M. Farrell, Leah N. Makley, Martin T. Zanni, Usha P Andley

Open Access Publications

αB-crystallin is a small heat shock protein that forms a heterooligomeric complex with αA-crystallin in the ocular lens. It is also widely distributed in tissues throughout the body and has been linked with neurodegenerative diseases such as Alzheimer's, where it is associated with amyloid fibrils. Crystallins can form amorphous aggregates in cataracts as well as more structured amyloid-like fibrils. The arginine 120 to glycine (R120G) mutation in αB-crystallin (Cryab-R120G) results in high molecular weight crystallin protein aggregates and loss of the chaperone activity of the protein in vitro, and it is associated with human hereditary cataracts and myopathy. Characterizing the …

Neuronal Activity In Dorsal Anterior Cingulate Cortex During Economic Choices Under Variable Action Costs, Xinying Cai, Camillo Padoa-Schioppa

Open Access Publications

The role of the dorsal anterior cingulate cortex (ACCd) in decision making has often been discussed but remains somewhat unclear. On the one hand, numerous studies implicated this area in decisions driven by effort or action cost. On the other hand, work on economic choices between goods (under fixed action costs) found that neurons in ACCd encoded only post-decision variables. To advance our understanding of the role played by this area in decision making, we trained monkeys to choose between different goods (juice types) offered in variable amounts and with different action costs. Importantly, the task design dissociated computation of …

Information Content Differentiates Enhancers From Silencers In Mouse Photoreceptors, Ryan Z. Friedman, David M. Granas, Connie A. Myers, Joseph C. Corbo, Barak A. Cohen, Michael A. White

Open Access Publications

Enhancers and silencers often depend on the same transcription factors (TFs) and are conflated in genomic assays of TF binding or chromatin state. To identify sequence features that distinguish enhancers and silencers, we assayed massively parallel reporter libraries of genomic sequences targeted by the photoreceptor TF cone-rod homeobox (CRX) in mouse retinas. Both enhancers and silencers contain more TF motifs than inactive sequences, but relative to silencers, enhancers contain motifs from a more diverse collection of TFs. We developed a measure of information content that describes the number and diversity of motifs in a sequence and found that, while both …

Acaricidal Activity Of Foeniculum Vulgare Against Rhipicephalus Annulatus Is Mainly Dependent On Its Constituent From Trans-Anethone, Shawky M. Aboelhadid, Waleed M. Arafa, Abdel-Azeem S. Abdel-Baki, Atalay Sokmen, Saleh Al-Quraishy, Ahmed O. Hassan, Asmaa A. Kamel

Open Access Publications

Globally, the economic losses due to hard ticks infestation and the control of the associated diseases have been calculated at USD $13.9-18.7 billion per year. The economic impact is related to its direct damage to the skins, blood loss, anemia, severe immunological reactions and indirect losses that related to the effects of hemoparasites, cost of treatment for clinical cases and expenses incurred in the control of ticks. The current study evaluated the acaricidal activities of fennel Foeniculum vulgare essential oil and its main components; trans-anethole and fenchone; against R. annulatus. GC-MS analysis revealed that this oil contained 16 components representing …

Diffusion Basis Spectrum Imaging Measures Anti-Inflammatory And Neuroprotective Effects Of Fingolimod On Murine Optic Neuritis, Ruimeng Yang, Tsen-Hsuan Lin, Jie Zhan, Shengsheng Lai, Chunyu Song, Peng Sun, Zezhong Ye, Michael Wallendorf, Ajit George, Anne H Cross, Sheng-Kwei Song

Open Access Publications

OBJECTIVE: To prospectively determine whether diffusion basis spectrum imaging (DBSI) detects, differentiates and quantitates coexisting inflammation, demyelination, axonal injury and axon loss in mice with optic neuritis (ON) due to experimental autoimmune encephalomyelitis (EAE), and to determine if DBSI accurately measures effects of fingolimod on underlying pathology.

METHODS: EAE was induced in 7-week-old C57BL/6 female mice. Visual acuity (VA) was assessed daily to detect onset of ON after which daily oral-treatment with either fingolimod (1 mg/kg) or saline was given for ten weeks. In vivo DBSI scans of optic nerves were performed at baseline, 2-, 6- and 10-weeks post treatment. …

Live Imaging Reveals The Cellular Events Downstream Of Sarm1 Activation, Kwang Woo Ko, Laura Devault, Yo Sasaki, Jeffrey Milbrandt, Aaron Diantonio

Open Access Publications

SARM1 is an inducible NAD

Intestinal Goblet Cells Sample And Deliver Lumenal Antigens By Regulated Endocytic Uptake And Transcytosis, Jenny K. Gustafsson, Jazmyne E. Davis, Tracy Rappai, Keely G. Mcdonald, Devesha H. Kulkarni, Kathryn A. Knoop, Simon P. Hogan, James A.J. Fitzpatrick, Wayne I. Lencer, Rodney D. Newberry

Open Access Publications

Intestinal goblet cells maintain the protective epithelial barrier through mucus secretion and yet sample lumenal substances for immune processing through formation of goblet cell associated antigen passages (GAPs). The cellular biology of GAPs and how these divergent processes are balanced and regulated by goblet cells remains unknown. Using high-resolution light and electron microscopy, we found that in mice, GAPs were formed by an acetylcholine (ACh)-dependent endocytic event remarkable for delivery of fluid-phase cargo retrograde into the trans-golgi network and across the cell by transcytosis - in addition to the expected transport of fluid-phase cargo by endosomes to multi-vesicular bodies and …

Bcl6 Controls Meningeal Th17–B Cell Interaction In Murine Neuroinflammation, Maike Hartlehnert, Gregory F. Wu, Et Al

Open Access Publications

No abstract provided.

Processing Pipeline For Image Reconstructed Fnirs Analysis Using Both Mri Templates And Individual Anatomy, Samuel Forbes, Sobanawartiny Wijeakumar, Adam Eggebrecht, Vincent Magnotta, John Spencer

Open Access Publications

No abstract provided.

Pet Study Of Sphingosine-1-Phosphate Receptor 1 Expression In Response To S. Aureus Infection, Hao Jiang, Jiwei Gu, Haiyang Zhao, Sumit Joshi, Joel Perlmutter, Robert Gropler, Robyn Klein, Tammie Benzinger, Zhude Tu

Open Access Publications

Sphingosine-1-phosphate receptor 1 (S1PR1) plays a crucial role in infectious diseases. Targeting S1PR1 provides protection against pathogens, such as influenza viruses. This study is aimed at investigating S1PR1 in response to bacterial infection by assessing S1PR1 expression in

A Proinflammatory Stimulus Disrupts Hippocampal Plasticity And Learning Via Microglial Activation And 25-Hydroxycholesterol, Yukitoshi Izumi, Anil G. Cashikar, Kathiresan Krishnan, Steven M. Paul, Douglas F. Covey, Steven J. Mennerick, Charles F. Zorumski

Open Access Publications

Inflammatory cells, including macrophages and microglia, synthesize and release the oxysterol 25-hydroxycholesterol (25HC), which has antiviral and immunomodulatory properties. Here, we examined the effects of lipopolysaccharide (LPS), an activator of innate immunity, on 25HC production in microglia, and the effects of LPS and 25HC on CA1 hippocampal synaptic plasticity and learning. In primary microglia, LPS markedly increases the expression of cholesterol 25-hydroxylase (Ch25h), the key enzyme involved in 25HC synthesis, and increases the levels of secreted 25HC. Wild-type microglia produced higher levels of 25HC than

A Randomized, Placebo-Controlled Trial Assessing The Effect Of Visbiome Es Probiotic In People With Hiv On Antiretroviral Therapy, Rachel M. Presti, Et Al

Open Access Publications

Background: A5350, a phase II, randomized, double-blind study, evaluated the safety and tolerability of the probiotic Visbiome Extra Strength (ES) over 24 weeks and measured effects on inflammation and intestinal barrier function.

Methods: The primary outcome was change in soluble CD14 (sCD14) levels; secondary outcomes included safety and tolerability, markers of inflammation and cellular activation, and microbiome. In a substudy, gut permeability was assessed by paired colonic biopsies measuring the area of lamina propria occupied by CD4+ cells, interleukin (IL)-17+ cells, and myeloperoxidase (MPO). Changes between arms were compared with the 2-sample

Results: Overall, 93 participants enrolled: 86% male, median …

Inhibitor Of Growth Protein 3 Epigenetically Silences Endogenous Retroviral Elements And Prevents Innate Immune Activation, Yanhua Song, Gaopeng Hou, Jonathan Diep, Yaw Shin Ooi, Natalia S. Akopyants, Stephen M. Beverley, Jan E. Carette, Harry B. Greenberg, Siyuan Ding

Open Access Publications

Endogenous retroviruses (ERVs) are subject to transcriptional repression in adult tissues, in part to prevent autoimmune responses. However, little is known about the epigenetic silencing of ERV expression. Here, we describe a new role for inhibitor of growth family member 3 (ING3), to add to an emerging group of ERV transcriptional regulators. Our results show that ING3 binds to several ERV promoters (for instance MER21C) and establishes an EZH2-mediated H3K27 trimethylation modification. Loss of ING3 leads to decreases of H3K27 trimethylation enrichment at ERVs, induction of MDA5-MAVS-interferon signaling, and functional inhibition of several virus infections. These data demonstrate an important …

Coronavirus Disease 2019-Associated Invasive Fungal Infection, John W. Baddley, George R. Thompson, Sharon C.-A. Chen, P. Lewis White, Melissa D. Johnson, M. Hong Nguyen, Ilan S. Schwartz, Andrej Spec, Luis Ostrosky-Zeichner, Brendan R. Jackson, Thomas F. Patterson, Peter G. Pappas

Open Access Publications

Coronavirus disease 2019 (COVID-19) can become complicated by secondary invasive fungal infections (IFIs), stemming primarily from severe lung damage and immunologic deficits associated with the virus or immunomodulatory therapy. Other risk factors include poorly controlled diabetes, structural lung disease and/or other comorbidities, and fungal colonization. Opportunistic IFI following severe respiratory viral illness has been increasingly recognized, most notably with severe influenza. There have been many reports of fungal infections associated with COVID-19, initially predominated by pulmonary aspergillosis, but with recent emergence of mucormycosis, candidiasis, and endemic mycoses. These infections can be challenging to diagnose and are associated with poor outcomes. …

The Genetic Architecture Of A Congenital Heart Defect Is Related To Its Fitness Cost, Ehiole Akhirome, Suk D Regmi, Rachel A Magnan, Nelson Ugwu, Yidan Qin, Claire E Schulkey, James M Cheverud, Patrick Y Jay

Open Access Publications

In newborns, severe congenital heart defects are rarer than mild ones. This epidemiological relationship between heart defect severity and incidence lacks explanation. Here, an analysis of ~10,000

Toxoplasma Bradyzoites Exhibit Physiological Plasticity Of Calcium And Energy Stores Controlling Motility And Egress, Yong Fu, Kevin M. Brown, Nathaniel G. Jones, Silvia N.J. Moreno, L. David Sibley

Open Access Publications

No abstract provided.

Cell Death And Transcriptional Responses Induced In Larvae Of The Nematode Haemonchus Contortus By Toxins/Toxicants With Broad Phylogenetic Efficacy, Douglas P Jasmer, Bruce A Rosa, Makedonka Mitreva

Open Access Publications

Establishing methods to investigate treatments that induce cell death in parasitic nematodes will promote experimental approaches to elucidate mechanisms and to identify prospective anthelmintics capable of inducing this outcome. Here, we extended recent progress on a method to monitor cell death and to identify small molecule inhibitors in

A Comprehensive Review Of Tic Disorders In Children, Keisuke Ueda, Kevin J. Black

Open Access Publications

Tics are characterized by sudden, rapid, recurrent, nonrhythmic movement or vocalization, and are the most common movement disorders in children. Their onset is usually in childhood and tics often will diminish within one year. However, some of the tics can persist and cause various problems such as social embarrassment, physical discomfort, or emotional impairments, which could interfere with daily activities and school performance. Furthermore, tic disorders are frequently associated with comorbid neuropsychiatric symptoms, which can become more problematic than tic symptoms. Unfortunately, misunderstanding and misconceptions of tic disorders still exist among the general population. Understanding tic disorders and their comorbidities …

Vaccines For Protecting Infants From Bacterial Causes Of Diarrheal Disease, Richard Walker, Robert W Kaminski, Chad Porter, Robert K M Choy, Jessica A White, James M Fleckenstein, Fred Cassels, Louis Bourgeois

Open Access Publications

The global diarrheal disease burden for

Toll-Like Receptor Signaling In The Establishment And Function Of The Immune System, Jahnavi Aluri, Megan A Cooper, Laura G Schuettpelz

Open Access Publications

Toll-like receptors (TLRs) are pattern recognition receptors that play a central role in the development and function of the immune system. TLR signaling promotes the earliest emergence of hematopoietic cells during development, and thereafter influences the fate and function of both primitive and effector immune cell types. Aberrant TLR signaling is associated with hematopoietic and immune system dysfunction, and both loss- and gain-of- function variants in TLR signaling-associated genes have been linked to specific infection susceptibilities and immune defects. Herein, we will review the role of TLR signaling in immune system development and the growing number of heritable defects in …

Flexor Tendon Injury And Repair: The Influence Of Synovial Environment On The Early Healing Response In A Canine Mode, Hua Shen, Susumu Yoneda, Shelly E Sakiyama-Elbert, Qiang Zhang, Stavros Thomopoulos, Richard H Gelberman

Open Access Publications

BACKGROUND: Environmental conditions strongly influence the healing capacity of connective tissues. Well-vascularized extrasynovial tendons typically undergo a robust wound-healing process following transection and repair. In contrast, avascular intrasynovial tendons do not mount an effective repair response. The current study tests the hypothesis that flexor tendons, as a function of their synovial environment, exhibit unique inflammatory, angiogenic, and metabolic responses to injury and repair.

METHODS: Flexor tendons present a distinct opportunity to test the study hypothesis, as they have proximal regions that are extrasynovial and distal regions that are intrasynovial. In an internally controlled study design, the second and fifth forepaw …

Eruptive Xanthoma Model Reveals Endothelial Cells Internalize And Metabolize Chylomicrons, Leading To Extravascular Triglyceride Accumulation, Ainara G Cabodevilla, Songtao Tang, Sungwoon Lee, Adam E Mullick, Jose O Aleman, M Mahmood Hussain, William C Sessa, Nada A Abumrad, Ira J Goldberg

Open Access Publications

Although tissue uptake of fatty acids from chylomicrons is primarily via lipoprotein lipase (LpL) hydrolysis of triglycerides (TGs), studies of patients with genetic LpL deficiency suggest additional pathways deliver dietary lipids to tissues. Despite an intact endothelial cell (EC) barrier, hyperchylomicronemic patients accumulate chylomicron-derived lipids within skin macrophages, leading to the clinical finding eruptive xanthomas. We explored whether an LpL-independent pathway exists for transfer of circulating lipids across the EC barrier. We found that LpL-deficient mice had a marked increase in aortic EC lipid droplets before and after a fat gavage. Cultured ECs internalized chylomicrons, which were hydrolyzed within lysosomes. …

Nanoparticulate Matter Exposure Results In White Matter Damage And An Inflammatory Microglial Response In An Experimental Murine Model, Michelle Connor, Krista Lamorie-Foote, Qinghai Liu, Kristina Shkirkova, Hans Baertsch, Constantinos Sioutas, Todd E. Morgan, Caleb E. Finch, William J. Mack

Open Access Publications

Exposure to ambient air pollution has been associated with white matter damage and neurocognitive decline. However, the mechanisms of this injury are not well understood and remain largely uncharacterized in experimental models. Prior studies have shown that exposure to particulate matter (PM), a sub-fraction of air pollution, results in neuroinflammation, specifically the upregulation of inflammatory microglia. This study examines white matter and axonal injury, and characterizes microglial reactivity in the corpus callosum of mice exposed to 10 weeks (150 hours) of PM. Nanoscale particulate matter (nPM, aerodynamic diameter ≤200 nm) consisting primarily of traffic-related emissions was collected from an urban …