Digital Commons Network^™

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 …

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

Human B Cell Lineages Associated With Germinal Centers Following Influenza Vaccination Are Measurably Evolving, Kenneth B. Hoehn, Jackson S. Turner, Frederick I. Miller, Ruoyi Jiang, Oliver G. Pybus, Ali H. Ellebedy, Steven H. Kleinstein

Open Access Publications

The poor efficacy of seasonal influenza virus vaccines is often attributed to pre-existing immunity interfering with the persistence and maturation of vaccine-induced B cell responses. We previously showed that a subset of vaccine-induced B cell lineages are recruited into germinal centers (GCs) following vaccination, suggesting that affinity maturation of these lineages against vaccine antigens can occur. However, it remains to be determined whether seasonal influenza vaccination stimulates additional evolution of vaccine-specific lineages, and previous work has found no significant increase in somatic hypermutation among influenza-binding lineages sampled from the blood following seasonal vaccination in humans. Here, we investigate this issue …

The Shu Complex Prevents Mutagenesis And Cytotoxicity Of Single-Strand Specific Alkylation Lesions, Braulio Bonilla, Hani S. Zaher, Nima Mosammaparast, Et Al

Open Access Publications

Three-methyl cytosine (3meC) are toxic DNA lesions, blocking base pairing. Bacteria and humans express members of the AlkB enzymes family, which directly remove 3meC. However, other organisms, including budding yeast, lack this class of enzymes. It remains an unanswered evolutionary question as to how yeast repairs 3meC, particularly in single-stranded DNA. The yeast Shu complex, a conserved homologous recombination factor, aids in preventing replication-associated mutagenesis from DNA base damaging agents such as methyl methanesulfonate (MMS). We found that MMS-treated Shu complex-deficient cells exhibit a genome-wide increase in A:T and G:C substitutions mutations. The G:C substitutions displayed transcriptional and replicational asymmetries …

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.

Functional Implications Of The Dynamic Regulation Of Epcam During Epithelial-To-Mesenchymal Transition, Taylor C Brown, Narendra V Sankpal, William E Gillanders

Open Access Publications

Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein expressed in epithelial tissues. EpCAM forms intercellular, homophilic adhesions, modulates epithelial junctional protein complex formation, and promotes epithelial tissue homeostasis. EpCAM is a target of molecular therapies and plays a prominent role in tumor biology. In this review, we focus on the dynamic regulation of EpCAM expression during epithelial-to-mesenchymal transition (EMT) and the functional implications of EpCAM expression on the regulation of EMT. EpCAM is frequently and highly expressed in epithelial cancers, while silenced in mesenchymal cancers. During EMT, EpCAM expression is downregulated by extracellular signal-regulated kinases (ERK) and EMT transcription …

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. …

Isolation And Characterization Of A Novel Bacteriophage Wo From Allonemobius Socius Crickets In Missouri, Jonah Kupritz, John Martin, Kerstin Fischer, Kurt C. Curtis, Joseph R. Fauver, Yuefang Huang, Young-Jun Choi, Wandy L. Beatty, Makedonka Mitreva, Peter U. Fischer

Open Access Publications

Wolbachia are endosymbionts of numerous arthropod and some nematode species, are important for their development and if present can cause distinct phenotypes of their hosts. Prophage DNA has been frequently detected in Wolbachia, but particles of Wolbachia bacteriophages (phage WO) have been only occasionally isolated. Here, we report the characterization and isolation of a phage WO of the southern ground cricket, Allonemobius socius, and provided the first whole-genome sequence of phage WO from this arthropod family outside of Asia. We screened A. socius abdomen DNA extracts from a cricket population in eastern Missouri by quantitative PCR for Wolbachia surface protein …

Prognostic And Pathophysiologic Significance Of Il-8 (Cxcl8) In Biliary Atresia, Nimish Godbole, Iiris Nyholm, Maria Hukkinen, Joseph R Davidson, Athanasios Tyraskis, Katja Eloranta, Noora Andersson, Jouko Lohi, Päivi Heikkilä, Antti Kyrönlahti, Marjut Pihlajoki, Mark Davenport, Markku Heikinheimo, Mikko P Pakarinen

Open Access Publications

Interleukin (IL)-8 (CXCL8), a chemokine involved in neutrophil recruitment, has been implicated in ductular reaction and liver fibrogenesis. We studied liver and serum IL-8 expression in a large biliary atresia (BA) cohort and explored its prognostic and pathophysiological potential. IL-8 expression was assessed in liver utilizing quantitative polymerase chain reaction (qPCR), immunohistochemistry and in situ hybridization and in serum using an enzyme-linked immunosorbent assay, among 115 BA patients, 10 disease controls and 68 normal controls. Results were correlated to portoenterostomy (PE) outcomes, biochemical and histological liver injury, transcriptional markers of fibrosis and cholangiocytes, and expression of other related cytokines. IL-8 …

Role Of Anesthetics And Their Adjuvants In Neurovascular Protection In Secondary Brain Injury After Aneurysmal Subarachnoid Hemorrhage, Umeshkumar Athiraman, Gregory J Zipfel

Open Access Publications

Aneurysmal rupture accounts for the majority of subarachnoid hemorrhage and is responsible for most cerebrovascular deaths with high mortality and morbidity. Initial hemorrhage severity and secondary brain injury due to early brain injury and delayed cerebral ischemia are the major determinants of outcomes after aneurysmal subarachnoid hemorrhage. Several therapies have been explored to prevent these secondary brain injury processes after aneurysmal subarachnoid hemorrhage with limited clinical success. Experimental and clinical studies have shown a neuroprotective role of certain anesthetics in cerebrovascular disorders including aneurysmal subarachnoid hemorrhage. The vast majority of aneurysmal subarachnoid hemorrhage patients require general anesthesia for surgical or …

Basophils Balance Healing After Myocardial Infarction Via Il-4/Il-13, Florian Sicklinger, Kory J Lavine, Et Al

Open Access Publications

The inflammatory response after myocardial infarction (MI) is a precisely regulated process that greatly affects subsequent remodeling. Here, we show that basophil granulocytes infiltrated infarcted murine hearts, with a peak occurring between days 3 and 7. Antibody-mediated and genetic depletion of basophils deteriorated cardiac function and resulted in enhanced scar thinning after MI. Mechanistically, we found that basophil depletion was associated with a shift from reparative Ly6Clo macrophages toward increased numbers of inflammatory Ly6Chi monocytes in the infarcted myocardium. Restoration of basophils in basophil-deficient mice by adoptive transfer reversed this proinflammatory phenotype. Cellular alterations in the absence of basophils were …

Investigation Of Convergent And Divergent Genetic Influences Underlying Schizophrenia And Alcohol Use Disorder, Emma C Johnson, Alexander S Hatoum, Sarah Hartz, Arpana Agrawal, Et Al

Open Access Publications

BACKGROUND: Alcohol use disorder (AUD) and schizophrenia (SCZ) frequently co-occur, and large-scale genome-wide association studies (GWAS) have identified significant genetic correlations between these disorders.

METHODS: We used the largest published GWAS for AUD (total cases = 77 822) and SCZ (total cases = 46 827) to identify genetic variants that influence both disorders (with either the same or opposite direction of effect) and those that are disorder specific.

RESULTS: We identified 55 independent genome-wide significant single nucleotide polymorphisms with the same direction of effect on AUD and SCZ, 8 with robust effects in opposite directions, and 98 with disorder-specific effects. …

The Fidelity Of Dna Replication, Particularly On Gc-Rich Templates, Is Reduced By Defects Of The Fe-S Cluster In Dna Polymerase Δ, Denis A. Kiktev, Margaret Dominska, Tony Zhang, Joseph Dahl, Elena I. Stepchenkova, Piotr Mieczkowski, Peter M. Burgers, Scott Lujan, Adam Burkholder, Thomas A. Kunkel, Thomas D. Petes

Open Access Publications

Iron-sulfur clusters (4Fe-4S) exist in many enzymes concerned with DNA replication and repair. The contribution of these clusters to enzymatic activity is not fully understood. We identified the MET18 (MMS19) gene of Saccharomyces cerevisiae as a strong mutator on GC-rich genes. Met18p is required for the efficient insertion of iron-sulfur clusters into various proteins. met18 mutants have an elevated rate of deletions between short flanking repeats, consistent with increased DNA polymerase slippage. This phenotype is very similar to that observed in mutants of POL3 (encoding the catalytic subunit of Pol δ) that weaken binding of the iron-sulfur cluster. Comparable mutants …

Weekend Light Shifts Evoke Persistent Drosophila Circadian Neural Network Desynchrony, Ceazar Nave, Logan Roberts, Patrick Hwu, Jerson D. Estrella, Thanh C. Vo, Thanh H. Nguyen, Tony Thai Bui, Daniel J. Rindner, Nicholas Pervolarakis, Paul J. Shaw, Tanya L. Leise, Todd C. Holmes

Open Access Publications

We developed a method for single-cell resolution longitudinal bioluminescence imaging of PERIOD (PER) protein and TIMELESS (TIM) oscillations in cultured male adult

Effects Of Gynura Bicolor On Glycemic Control And Antioxidant Ability In Prediabetes, Chu-Hsuan Hsia, Yu-Tang Tung, Yu-Sheng Yeh, Yi-Wen Chien

Open Access Publications

No abstract provided.

Early Aberrant Angiogenesis Due To Elastic Fiber Fragmentation In Aortic Valve Disease, Robert B Hinton, Amy L Juraszek, Amy M Opoka, Benjamin J Landis, J Michael Smith, Robert P Mecham, Kevin E Bove

Open Access Publications

Elastic fiber fragmentation (EFF) is a hallmark of aortic valve disease (AVD), and neovascularization has been identified as a late finding related to inflammation. We sought to characterize the relationship between early EFF and aberrant angiogenesis. To examine disease progression, regional anatomy and pathology of aortic valve tissue were assessed using histochemistry, immunohistochemistry, and electron microscopy from early-onset (<40 yo) and late-onset (≥40 yo) non-syndromic AVD specimens. To assess the effects of EFF on early AVD processes, valve tissue from Williams and Marfan syndrome patients was also analyzed. Bicuspid aortic valve was more common in early-onset AVD, and cardiovascular comorbidities were more common in late-onset AVD. Early-onset AVD specimens demonstrated angiogenesis without inflammation or atherosclerosis. A distinct pattern of elastic fiber components surrounded early-onset AVD neovessels, including increased emilin-1 and decreased fibulin-5. Different types of EFF were present in Williams syndrome (WS) and Marfan syndrome (MFS) aortic valves; WS but not MFS aortic valves demonstrated angiogenesis. Aberrant angiogenesis occurs in early-onset AVD in the absence of inflammation, implicating EFF. Elucidation of underlying mechanisms may inform the development of new pharmacologic treatments.

Models Of Distal Arthrogryposis And Lethal Congenital Contracture Syndrome, Julia Whittle, Aaron Johnson, Matthew B Dobbs, Christina A Gurnett

Open Access Publications

Distal arthrogryposis and lethal congenital contracture syndromes describe a broad group of disorders that share congenital limb contractures in common. While skeletal muscle sarcomeric genes comprise many of the first genes identified for Distal Arthrogyposis, other mechanisms of disease have been demonstrated, including key effects on peripheral nerve function. While Distal Arthrogryposis and Lethal Congenital Contracture Syndromes display superficial similarities in phenotype, the underlying mechanisms for these conditions are diverse but overlapping. In this review, we discuss the important insights gained into these human genetic diseases resulting from in vitro molecular studies and in vivo models in fruit fly, zebrafish, …

Protein Phosphatase 4 Controls Circadian Clock Dynamics By Modulating Clock/Bmal1 Activity, Sabrina Klemz, Thomas Wallach, Sandra Korge, Mechthild Rosing, Roman Klemz, Bert Maier, Nicholas C Fiorenza, Irem Kaymak, Anna K Fritzsche, Erik D Herzog, Ralf Stanewsky, Achim Kramer

Open Access Publications

In all organisms with circadian clocks, post-translational modifications of clock proteins control the dynamics of circadian rhythms, with phosphorylation playing a dominant role. All major clock proteins are highly phosphorylated, and many kinases have been described to be responsible. In contrast, it is largely unclear whether and to what extent their counterparts, the phosphatases, play an equally crucial role. To investigate this, we performed a systematic RNAi screen in human cells and identified protein phosphatase 4 (PPP4) with its regulatory subunit PPP4R2 as critical components of the circadian system in both mammals and

Developmental Variation In Testosterone: Cortisol Ratio Alters Cortical- And Amygdala-Based Cognitive Processes, Jimin Lew, Sherri Lee Jones, Christina Caccese, Isobel Orfi, Charlotte Little, Kelly N Botteron, James T Mccracken, Tuong-Vi Nguyen

Open Access Publications

Testosterone (T) and cortisol (C) are the end products of neuroendocrine axes that interact with the process of shaping brain structure and function. Relative levels of T:C (TC ratio) may alter prefrontal-amygdala functional connectivity in adulthood. What remains unclear is whether TC-related effects are rooted to childhood and adolescence. We used a healthy cohort of 4-22-year-olds to test for associations between TC ratios, brain structure (amygdala volume, cortical thickness (CTh), and their coordinated growth), as well as cognitive and behavioral development. We found greater TC ratios to be associated with the growth of specific brain structures: 1) parietal CTh; 2) …

Bioactivation Of Isoxazole-Containing Bromodomain And Extra-Terminal Domain (Bet) Inhibitors, Noah R Flynn, Michael D Ward, Mary A Schleiff, Corentine M C Laurin, Rohit Farmer, Stuart J Conway, Gunnar Boysen, S Joshua Swamidass, Grover P Miller

Open Access Publications

The 3,5-dimethylisoxazole motif has become a useful and popular acetyl-lysine mimic employed in isoxazole-containing bromodomain and extra-terminal (BET) inhibitors but may introduce the potential for bioactivations into toxic reactive metabolites. As a test, we coupled deep neural models for quinone formation, metabolite structures, and biomolecule reactivity to predict bioactivation pathways for 32 BET inhibitors and validate the bioactivation of select inhibitors experimentally. Based on model predictions, inhibitors were more likely to undergo bioactivation than reported non-bioactivated molecules containing isoxazoles. The model outputs varied with substituents indicating the ability to scale their impact on bioactivation. We selected OXFBD02, OXFBD04, and I-BET151 …

Rp11-362k2.2:Rp11-767i20.1 Genetic Variation Is Associated With Post-Reperfusion Therapy Parenchymal Hematoma. A Gwas Meta-Analysis, Elena Muiño, Laura Heitsch, Laura Ibañez, Carlos Cruchaga, Rajat Dhar, Jin-Moo Lee, Et Al

Open Access Publications

Stroke is one of the most common causes of death and disability. Reperfusion therapies are the only treatment available during the acute phase of stroke. Due to recent clinical trials, these therapies may increase their frequency of use by extending the time-window administration, which may lead to an increase in complications such as hemorrhagic transformation, with parenchymal hematoma (PH) being the more severe subtype, associated with higher mortality and disability rates. Our aim was to find genetic risk factors associated with PH, as that could provide molecular targets/pathways for their prevention/treatment and study its genetic correlations to find traits sharing …

Ser 71 Phosphorylation Inhibits Actin-Binding Of Profilin-1 And Its Apoptosis-Sensitizing Activity, Faliang Wang, Cuige Zhu, Shirong Cai, Aaron Boudreau, Sun-Joong Kim, Mina Bissell, Jieya Shao

Open Access Publications

The essential actin-binding factor profilin-1 (Pfn1) is a non-classical tumor suppressor with the abilities toboth inhibit cellular proliferation and augment chemotherapy-induced apoptosis. Besides actin, Pfn1 interacts with proteins harboring the poly-L-proline (PLP) motifs. Our recent work demonstrated that both nuclear localization and PLP-binding are required for tumor growth inhibition by Pfn1, and this is at least partially due to Pfn1 association with the PLP-containing ENL protein in the Super Elongation Complex (SEC) and the transcriptional inhibition of pro-cancer genes. In this paper, by identifying a phosphorylation event of Pfn1 at Ser

Using Monozygotic Twins To Dissect Common Genes In Posttraumatic Stress Disorder And Migraine, Charlotte K Bainomugisa, Heidi G Sutherland, Richard Parker, Allan F Mcrae, Larisa M Haupt, Lyn R Griffiths, Andrew Heath, Elliot C Nelson, Margaret J Wright, Ian B Hickie, Nicholas G Martin, Dale R Nyholt, Divya Mehta

Open Access Publications

Epigenetic mechanisms have been associated with genes involved in Posttraumatic stress disorder (PTSD). PTSD often co-occurs with other health conditions such as depression, cardiovascular disorder and respiratory illnesses. PTSD and migraine have previously been reported to be symptomatically positively correlated with each other, but little is known about the genes involved. The aim of this study was to understand the comorbidity between PTSD and migraine using a monozygotic twin disease discordant study design in six pairs of monozygotic twins discordant for PTSD and 15 pairs of monozygotic twins discordant for migraine. DNA from peripheral blood was run on Illumina EPIC …