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A Novel Rapamycin Analog Is Highly Selective For Mtorc1 In Vivo., Katherine H. Schreiber, Sebastian I. Arriola Apelo, Deyang Yu, Jacqueline A Brinkman, Michael C Velarde, Faizan A Syed, Chen-Yu Liao, Emma L. Baar, Kathryn A. Carbajal, Dawn S. Sherman, Denise Ortiz, Regina Brunauer, Shany E. Yang, Stelios T Tzannis, Brian K Kennedy, Dudley W Lamming

Natural Sciences and Mathematics | Student Professional Publications

Rapamycin, an inhibitor of mechanistic Target Of Rapamycin Complex 1 (mTORC1), extends lifespan and shows strong potential for the treatment of age-related diseases. However, rapamycin exerts metabolic and immunological side effects mediated by off-target inhibition of a second mTOR-containing complex, mTOR complex 2. Here, we report the identification of DL001, a FKBP12-dependent rapamycin analog 40x more selective for mTORC1 than rapamycin. DL001 inhibits mTORC1 in cell culture lines and in vivo in C57BL/6J mice, in which DL001 inhibits mTORC1 signaling without impairing glucose homeostasis and with substantially reduced or no side effects on lipid metabolism and the immune system. In …

A Sparse Covarying Unit That Describes Healthy And Impaired Human Gut Microbiota Development, Arjun S Raman, Jeanette L Gehrig, Siddarth Venkatesh, Hao-Wei Chang, Matthew C Hibberd, Sathish Subramanian, Michael J Barratt, Jeffrey I Gordon, Et Al

Open Access Publications

Characterizing the organization of the human gut microbiota is a formidable challenge given the number of possible interactions between its components. Using a statistical approach initially applied to financial markets, we measured temporally conserved covariance among bacterial taxa in the microbiota of healthy members of a Bangladeshi birth cohort sampled from 1 to 60 months of age. The results revealed an "ecogroup" of 15 covarying bacterial taxa that provide a concise description of microbiota development in healthy children from this and other low-income countries, and a means for monitoring community repair in undernourished children treated with therapeutic foods. Features of …

Effects Of Microbiota-Directed Foods In Gnotobiotic Animals And Undernourished Children, Jeanette L Gehrig, Siddarth Venkatesh, Hao-Wei Chang, Matthew C Hibberd, Vanderlene L Kung, Jiye Cheng, Robert Y Chen, Sathish Subramanian, Carrie A Cowardin, Martin F Meier, David O'Donnell, Michael Talcott, Larry D Spears, Clay F Semenkovich, Christopher Sawyer, Richard D Head, Michael J Barratt, Jeffrey I Gordon, Et Al

Open Access Publications

To examine the contributions of impaired gut microbial community development to childhood undernutrition, we combined metabolomic and proteomic analyses of plasma samples with metagenomic analyses of fecal samples to characterize the biological state of Bangladeshi children with severe acute malnutrition (SAM) as they transitioned, after standard treatment, to moderate acute malnutrition (MAM) with persistent microbiota immaturity. Host and microbial effects of microbiota-directed complementary food (MDCF) prototypes targeting weaning-phase bacterial taxa underrepresented in SAM and MAM microbiota were characterized in gnotobiotic mice and gnotobiotic piglets colonized with age- and growth-discriminatory bacteria. A randomized, double-blind controlled feeding study identified a lead MDCF …

In Vivo Effectiveness And Safety Of Probiotics On Prophylaxis And Treatment Of Oral Candidiasis: A Systematic Review And Meta-Analysis, Lijun Hu, Mimi Zhou, Andrew L. Young, Weiwei Zhao, Zhimin Yan

All Dugoni School of Dentistry Faculty Articles

BACKGROUND: To systematically review and assess the in vivo effectiveness and safety of probiotics for prophylaxis and treating oral candidiasis.

METHODS: A literature search for studies published in English until August 1, 2018 was conducted in the following databases: PubMed, EMBASE, Cochrane Library, and Web of Science. Randomized controlled clinical trials and experimental mouse animal model studies comparing probiotics (at any dosage and in any form) with control groups (placebo, blank control or other agents) and reporting outcomes of the prophylactic and therapeutic effects were considered for inclusion. A descriptive study and, potentially, a meta-analysis were planned.

RESULTS: Six randomized …

Wilgus, Donald Knight (Fa 1203), Manuscripts & Folklife Archives

Folklife Archives Finding Aids

Finding aid only for Folklife Archives Project 1203. Student folk studies projects collected by Professor Donald Knight “D. K.” Wilgus while teaching folk studies classes at Western Kentucky University. Most of the items collected are from south central Kentucky, but also includes items from Indiana, Ohio and Tennessee.

Born Bad, Jaimee Pease

Children's Book and Media Review

Born Bad is a playful story surrounding the struggles of identity. Wolf is unhappy in who he is supposed to be and wanders around the animal kingdom, hopeless that he will ever be able to change. Along his journey, he meets many animals, each with their own shortcomings. Only when he observes the self-confidence and mutual support of his new friends does Wolf find the courage to embrace who he wants to be. C.K. Smouha’s simple phrases and diverse characters pair vividly with Stephen Smith’s bold illustrations to offer a humorous spin on clichéd idioms.

The Book Of Dust #1: La Belle Sauvage, Emma Patton

Children's Book and Media Review

Malcolm Polstead doesn’t have much chance for adventure. His parents run an inn, and he keeps himself entertained by listening to the customers and watching them interact. He visits the nuns at the nearby priory, rides in his boat called La Belle Sauvage, and, of course, is very close with his daemon—a part of Malcolm’s own consciousness that exists in animal form and goes with him everywhere. But there is unrest brewing in Malcolm’s town, and he quickly finds himself involved. It all begins when a baby, Lyra, is brought to the priory to be sheltered and protected by the …

Cool Duck & Lots Of Hats, Liz Kazandzhy

Children's Book and Media Review

This two-in-one early reader book combines simple stories with amusing illustrations that will surely captivate young readers. The first story begins with a hot cat, a hot dog, and a cool duck. When the cat ends up chasing the duck into the pond, with the dog following closely behind, they all get the benefit of cooling off in the water. In the second story, a boy and his parents are on a hike with their dog when the wind blows each of their hats off—first Sam’s “big hat,” then Dad’s “big, big hat,” and finally Mom’s “big, big, big hat.” …

Beware Of The Crocodile, Taran Burnett

Children's Book and Media Review

Imagine that you notice some squinty eyes and a snout poking out of the water—it is a crocodile waiting for his next meal! Beware of the Crocodile is an informational book that discusses the sharp teeth, eating patterns, and care of baby crocodiles. The gruesome details of how a crocodile eats are not included, but descriptive verbs like lunge, splash, and thrash give the reader an idea of what meal time is like. Learning that crocodiles can go weeks without food if they have a large meal is fascinating. Additionally, intriguing facts about how a mother crocodile cares for its …

Dear Professor Whale, Danielle Dallas

Children's Book and Media Review

Enjoying the clear blue sky or the dazzling ultramarine of the ocean may not be enough for retired Professor Whale anymore. He has written letters to unknown recipients across the ocean and is eagerly awaiting responses. One letter comes from an adolescent whale whose grandfather knew Professor Whale. Other responses come from Professor Whale's friends themselves who decided to return for a reunion when they received Professor Whale's letters. Inspired by his young pen pal, Professor Whale and his friends reinstate the Whale Point Olympics where the new generation learn that it's more about friendship and supporting each other than …

Jojo And The Food Fight!, Leah Christopher

Children's Book and Media Review

When the jungle explodes into a food fight, one animal chooses to take creative action to stop it. Braving the frenzy of flying food, Jojo the elephant appears on the scene claiming to have lost his memory—he can’t even recall what a banana is! The lion, monkey, and crocodile, hippopotamus, and others take a timeout to sit down with Jojo. He tries to get to the bottom of the food fight—why did it start? At first, the animals blame each other, but as they eat their bananas, some begin to offer up their fruits to share. They all reminisce about …

Plasticizer Interaction With The Heart: Chemicals Used In Plastic Medical Devices Can Interfere With Cardiac Electrophysiology., Rafael Jaimes, Damon Mccullough, Bryan Siegel, Luther Swift, Daniel Mcinerney, James Hiebert, Erick A Perez-Alday, Beatriz Trenor, Jiansong Sheng, Javier Saiz, Larisa G Tereshchenko, Nikki Gillum Posnack

Pediatrics Faculty Publications

BACKGROUND: Phthalates are used as plasticizers in the manufacturing of flexible, plastic medical products. Patients can be subjected to high phthalate exposure through contact with plastic medical devices. We aimed to investigate the cardiac safety and biocompatibility of mono-2-ethylhexyl phthalate (MEHP), a phthalate with documented exposure in intensive care patients.

METHODS: Optical mapping of transmembrane voltage and pacing studies were performed on isolated, Langendorff-perfused rat hearts to assess cardiac electrophysiology after MEHP exposure compared with controls. MEHP dose was chosen based on reported blood concentrations after an exchange transfusion procedure.

RESULTS: Thirty-minute exposure to MEHP increased the atrioventricular node (147 …

A Guinea Fowl Genome Assembly Provides New Evidence On Evolution Following Domestication And Selection In Galliformes, Alain Vignal, Simon Boitard, Noémie Thébault, Guiguigbaza-Kossigan Dayo, Valentine Yapi-Gnaore, Issaka Youssao Abdou Karim, Cécile Berthouly-Salazar, Nóra Pálinkás-Bodzsár, Daniel Guémené, Francoise Thibaud-Nissen, Wesley C Warren, Michèle Tixier-Boichard, Xavier Rognon

Open Access Publications

The helmeted guinea fowl Numida meleagris belongs to the order Galliformes. Its natural range includes a large part of sub-Saharan Africa, from Senegal to Eritrea and from Chad to South Africa. Archaeozoological and artistic evidence suggest domestication of this species may have occurred about 2,000 years BP in Mali and Sudan primarily as a food resource, although villagers also benefit from its capacity to give loud alarm calls in case of danger, of its ability to consume parasites such as ticks and to hunt snakes, thus suggesting its domestication may have resulted from a commensal association process. Today, it is …

Phospholipases D: Making Sense Of Redundancy And Duplication, Andrew J. Morris

Internal Medicine Faculty Publications

Why have two genes when one would suffice? Evolutionary pressure means that biology, unlike government, is generally intolerant of wasted effort. Therefore, when multiple genes exist presumably they are there to provide some benefit to the organism even if that benefit is not immediately obvious to us scientists. A recent report from Raghu and colleagues (Biosci. Rep. (2018) 38, pii: BSR20181690) [1] sheds some light on one possible reason for the existence of two Phospholipases D genes in chordates when only one is present in invertebrates.

Pathologic Gene Network Rewiring Implicates Ppp1r3a As A Central Regulator In Pressure Overload Heart Failure., Pablo Cordero, Victoria N Parikh, Elizabeth T Chin, Ayca Erbilgin, Michael J Gloudemans, Ching Shang, Yong Huang, Alex C Chang, Kevin S Smith, Frederick Dewey, Kathia Zaleta, Michael Morley, Jeff Brandimarto, Nicole Glazer, Daryl Waggott, Aleksandra Pavlovic, Mingming Zhao, Christine S Moravec, W H Wilson Tang, Jamie Skreen, Christine Malloy, Sridhar Hannenhalli, Hongzhe Li, Scott Ritter, Mingyao Li, Daniel Bernstein, Andrew Connolly, Hakon Hakonarson, Aldons J Lusis, Kenneth B Margulies, Anna A Depaoli-Roach, Stephen B Montgomery, Matthew T Wheeler, Thomas Cappola, Euan A Ashley

Articles, Abstracts, and Reports

Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvest 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtain genome-wide genotyping and gene expression measurements for a subset of 313. We build failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerges as a regulator whose network connectivity changes significantly between health and disease. RNA sequencing after PPP1R3A knockdown validates network-based predictions, and highlights metabolic pathway regulation associated with increased cardiomyocyte size and …

Environmental Microcystin Targets The Microbiome And Increases The Risk Of Intestinal Inflammatory Pathology Via Nox2 In Underlying Murine Model Of Nonalcoholic Fatty Liver Disease, Sutapa Sarkar, Diana Kimono, Muayad Albadrani, Ratanesh K. Seth, Philip Busbee, Hasan Alghetaa, Dwayne E. Porter, Geoff I. Scott, Bryan Brooks, Mitzi Nagarkatti, Prakash Nagarkatti, Saurabh Chatterjee

Faculty Publications

With increased climate change pressures likely to influence harmful algal blooms, exposure to microcystin, a known hepatotoxin and a byproduct of cyanobacterial blooms can be a risk factor for NAFLD associated comorbidities. Using both in vivo and in vitro experiments we show that microcystin exposure in NAFLD mice cause rapid alteration of gut microbiome, rise in bacterial genus known for mediating gut inflammation and lactate production. Changes in the microbiome were strongly associated with inflammatory pathology in the intestine, gut leaching, tight junction protein alterations and increased oxidative tyrosyl radicals. Increased lactate producing bacteria from the altered microbiome was associated …

Intracellular Retention Of Mutant Lysyl Oxidase Leads To Aortic Dilation In Response To Increased Hemodynamic Stress, Vivian S Lee, Carmen M Halabi, Thomas J Broekelmann, Philip C Trackman, Nathan O Stitziel, Robert P Mecham

Open Access Publications

Heterozygous missense mutations in lysyl oxidase (LOX) are associated with thoracic aortic aneurysms and dissections. To assess how LOX mutations modify protein function and lead to aortic disease, we studied the factors that influence the onset and progression of vascular aneurysms in mice bearing a Lox mutation (p.M292R) linked to aortic dilation in humans. We show that mice heterozygous for the M292R mutation did not develop aneurysmal disease unless challenged with increased hemodynamic stress. Vessel dilation was confined to the ascending aorta although both the ascending and descending aortae showed changes in vessel wall structure, smooth muscle cell number and …

Preoperative Stimulation Of Resolution And Inflammation Blockade Eradicates Micrometastases., Dipak Panigrahy, Allison Gartung, Jun Yang, Haixia Yang, Molly M Gilligan, Megan L Sulciner, Swati S Bhasin, Diane R Bielenberg, Jaimie Chang, Birgitta A Schmidt, Julia Piwowarski, Anna Fishbein, Dulce Soler-Ferran, Matthew A Sparks, Steven J Staffa, Vidula Sukhatme, Bruce D Hammock, Mark W Kieran, Sui Huang, Manoj Bhasin, Charles N Serhan, Vikas P Sukhatme

Articles, Abstracts, and Reports

Cancer therapy is a double-edged sword, as surgery and chemotherapy can induce an inflammatory/immunosuppressive injury response that promotes dormancy escape and tumor recurrence. We hypothesized that these events could be altered by early blockade of the inflammatory cascade and/or by accelerating the resolution of inflammation. Preoperative, but not postoperative, administration of the nonsteroidal antiinflammatory drug ketorolac and/or resolvins, a family of specialized proresolving autacoid mediators, eliminated micrometastases in multiple tumor-resection models, resulting in long-term survival. Ketorolac unleashed anticancer T cell immunity that was augmented by immune checkpoint blockade, negated by adjuvant chemotherapy, and dependent on inhibition of the COX-1/thromboxane A2 …

Xx Sex Chromosome Complement Promotes Atherosclerosis In Mice, Yasir Alsiraj, Xuqi Chen, Sean E. Thatcher, Ryan E. Temel, Lei Cai, Eric M. Blalock, Wendy Katz, Heba M. Ali, Michael C. Petriello, Pan Deng, Andrew J. Morris, Xuping Wang, Aldons J. Lusis, Arthur P. Arnold, Karen Reue, Katherine L. Thompson, Patrick Tso, Lisa A. Cassis

Pharmacology and Nutritional Sciences Faculty Publications

Men and women differ in circulating lipids and coronary artery disease (CAD). While sex hormones such as estrogens decrease CAD risk, hormone replacement therapy increases risk. Biological sex is determined by sex hormones and chromosomes, but effects of sex chromosomes on circulating lipids and atherosclerosis are unknown. Here, we use mouse models to separate effects of sex chromosomes and hormones on atherosclerosis, circulating lipids and intestinal fat metabolism. We assess atherosclerosis in multiple models and experimental paradigms that distinguish effects of sex chromosomes, and male or female gonads. Pro-atherogenic lipids and atherosclerosis are greater in XX than XY mice, indicating …

Art For Animals: Visual Culture And Animal Advocacy, 1870-1914 By J. Keri Cronin, Gina M. Granter

The Goose

Teview of J. Keri Cronin's Art for Animals: Visual Culture and Animal Advocacy, 1870-1914

The Big, Angry Roar, Carly Atchley

Children's Book and Media Review

Zebras stamp and stomp when they’re angry. Hippos splatter and splash, and elephants trumpet. But what can a lion cub do when he’s so angry he feels he could burst? Cub gets in trouble when he fights with his sister and, looking to blow off steam, talks to different animals to try and discover what will make him feel better. Stomping just hurts his feet, and splashing makes him wet and smelly. He’s so mad at this point that he lets out a huge, angry ROAR—and causes a stampede. Cub is embarrassed and worried about the mess he’s caused, but …

Ribbit!, Karen Abbott

Children's Book and Media Review

A comical pig with good intentions wants to fit in at the pond. The pig situates itself on a nice sized rock in the middle of the pond and issues a healthy, loud "Ribbit" over the pond. Frogs gather around and wonder what is going on with this unusual pig. Is he mocking them? Is he confused? What can he possibly mean by this outrageous behavior? Soon the entire wild population of animals have gathered around. Only the wise old beetle can solve this mystery. But by the time they have found the beetle and returned to the rock the …

Extreme Longevity: Discovering Earth's Oldest Organisms, Emilee Bell

Children's Book and Media Review

Shuffle back in time with Jonathan, the 100+ year old tortoise, and witness the evolution of the automobile. Rest beneath the shade of centuries-old trees born when the glaciers melted on the American continent. Peek at the ocean organisms that roamed the earth before humans were even a thought. Kenney beguiles the reader with ancient timelines, winding the biological history of the world with the human history, tying said reader tightly and permanently with the longevity of the plants and animals of this world. Each chapter feels like an epic tale: lone organisms surviving chaos, hunters, pollution, and massive social …

Origami And Poetry: Inspired By Nature, Gabrielle Borg

Children's Book and Media Review

Quaint poems of nature are mixed with cute pictures and detailed instructions of how to fold origami in this short book. Each page includes a poem about something in nature, a picture of that thing, and easy-to-follow instructions on how to create it origami-style. Learn to make your favorite things from nature: a leaf, a fox, a minnow, a shell. Enjoy each poem as you work to create a piece of art that is all your own.

Beware The Mighty Bitey, Emily Garrett

Children's Book and Media Review

Mouse, Goat, and Bear are on their way to Cougar's party. Little do they know that the friendly piranhas under the rope bridge are actually trying to trick them into becoming lunch! The piranhas first stop Mouse and ask him to dance and play his ukulele for them, but he is quickly joined by Goat on his drum and Bear with his tuba! By this time, it is too much for the rope bridge to take, and they are all sent splashing into the water—much to the piranhas’ delight. Luckily for Mouse, Goat, and Bear, their great big splash is …

Reactive Microglia And Il1Β/Il-1r1-Signaling Mediate Neuroprotection In Excitotoxin-Damaged Mouse Retina, Levi Todd, Isabella Palazzo, Lilianna Suarez, Xiaoyu Liu, Leo Volkov, Thanh V Hoang, Warren A Campbell, Seth Blackshaw, Ning Quan, Andy J Fischer

Open Access Publications

BACKGROUND: Microglia and inflammation have context-specific impacts upon neuronal survival in different models of central nervous system (CNS) disease. Herein, we investigate how inflammatory mediators, including microglia, interleukin 1 beta (IL1β), and signaling through interleukin 1 receptor type 1 (IL-1R1), influence the survival of retinal neurons in response to excitotoxic damage.

METHODS: Excitotoxic retinal damage was induced via intraocular injections of NMDA. Microglial phenotype and neuronal survival were assessed by immunohistochemistry. Single-cell RNA sequencing was performed to obtain transcriptomic profiles. Microglia were ablated by using clodronate liposome or PLX5622. Retinas were treated with IL1β prior to NMDA damage and cell …

Eosinophils Downregulate Lung Alloimmunity By Decreasing Tcr Signal Transduction, Oscar Okwudiri Onyema, Yizhan Guo, Bayan Mahgoub, Qing Wang, Amir Manafi, Zhongcheng Mei, Anirban Banerjee, Dongge Li, Mark H. Stoler, Melissa T. Zaidi, Adam G. Schrum, Daniel Kreisel, Andrew E. Gelman, Elizabeth A. Jacobsen, Alexander Sasha Krupnick

Open Access Publications

Despite the accepted notion that granulocytes play a universally destructive role in organ and tissue grafts, it has been recently described that eosinophils can facilitate immunosuppression-mediated acceptance of murine lung allografts. The mechanism of eosinophil-mediated tolerance, or their role in regulating alloimmune responses in the absence of immunosuppression, remains unknown. Using lung transplants in a fully MHC-mismatched BALB/c (H2d) to C57BL/6 (H2b) strain combination, we demonstrate that eosinophils downregulate T cell-mediated immune responses and play a tolerogenic role even in the absence of immunosuppression. We further show that such downregulation depends on PD-L1/PD-1-mediated synapse formation between eosinophils and T cells. …

Cyclin C Regulated Oxidative Stress Responsive Transcriptome In Mus Musculus Embryonic Fibroblasts, David C Stieg, Kai-Ti Chang, Katrina F Cooper, Randy Strich

Rowan-Virtua School of Osteopathic Medicine Departmental Research

The transcriptional changes that occur in response to oxidative stress help direct the decision to maintain cell viability or enter a cell death pathway. Cyclin C-Cdk8 is a conserved kinase that associates with the RNA polymerase II Mediator complex that stimulates or represses transcription depending on the locus. In response to oxidative stress, cyclin C, but not Cdk8, displays partial translocation into the cytoplasm. These findings open the possibility that cyclin C relocalization is a regulatory mechanism governing oxidative stress-induced transcriptional changes. In the present study, the cyclin C-dependent transcriptome was determined and compared to transcriptional changes occurring in oxidatively …

Immunomodulatory Role Of Non-Neuronal Cholinergic Signaling In Myocardial Injury, Cibele Rocha-Resende, Carla Weinheimer, Geetika Bajpai, Luigi Adamo, Scot J. Matkovich, Joel Schilling, Philip M. Barger, Kory J. Lavine, Douglas L. Mann

Open Access Publications

Whereas prior studies have demonstrated an important immunomodulatory role for the neuronal cholinergic system in the heart, the role of the non-neuronal cholinergic system is not well understood. To address the immunomodulatory role of the non-neuronal cholinergic system in the heart we used a previously validated diphtheria toxin (DT)-induced cardiomyocyte ablation model (Rosa26-DTMlc2v-Cre mice). DT-injected Rosa26-DTMlc2v-Cre mice were treated with diluent or Pyridostigmine Bromide (PYR), a reversible cholinesterase inhibitor. PYR treatment resulted in increased survival and decreased numbers of MHC-IIlowCCR2+ macrophages in DT-injected Rosa26-DTMlc2v-Cre mice compared to diluent treated Rosa26-DTMlc2v-Cre mice. Importantly, the expression of CCL2/7 mRNA and protein was …

Pet First Aid And C.P.R., Central Washington University, Gretchen Taussig-Simpson

Brooks Library Events

Learn how to keep your pet safe and healthy.