Digital Commons Network^™

Free Cholesterol Bioavailability And Atherosclerosis, Rei J Abe, Jun-Ichi Abe, Minh T H Nguyen, Elizabeth A Olmsted-Davis, Abrar Mamun, Priyanka Banerjee, John P Cooke, Longhou Fang, Henry Pownall, Nhat-Tu Le

Faculty, Staff and Student Publications

Purpose of review: As both a cholesterol acceptor and carrier in the reverse cholesterol transport (RCT) pathway, high-density lipoprotein (HDL) is putatively atheroprotective. However, current pharmacological therapies to increase plasma HDL cholesterol (HDL-c) concentration have paradoxically failed to prevent or reduce atherosclerosis and cardiovascular disease (CVD). Given that free cholesterol (FC) transfer between surfaces of lipoproteins and cells is reversible, excess plasma FC can be transferred to the cells of peripheral tissue sites resulting in atherosclerosis. Here, we summarize potential mechanisms contributing to this paradox and highlight the role of excess free cholesterol (FC) bioavailability in atherosclerosis vs. atheroprotection.

Recent …

Targeting The Notch1-Myc-Cd44 Axis In Leukemia-Initiating Cells In T-All, Sujan Piya, Yaling Yang, Seemana Bhattacharya, Priyanka Sharma, Huaxian Ma, Hong Mu, Hua He, Vivian Ruvolo, Natalia Baran, R Eric Davis, Abhinav K Jain, Marina Konopleava, Hagop Kantarjian, Michael Andreeff, M James You, Gautam Borthakur

Faculty, Staff and Student Publications

The NOTCH1-MYC-CD44 axis integrates cell-intrinsic and extrinsic signaling to ensure the persistence of leukemia-initiating cells (LICs) in T-cell acute lymphoblastic leukemia (T-ALL) but a common pathway to target this circuit is poorly defined. Bromodomain-containing protein 4 (BRD4) is implicated to have a role in the transcriptional regulation of oncogenes MYC and targets downstream of NOTCH1, and here we demonstrate its role in transcriptional regulation of CD44. Hence, targeting BRD4 will dismantle the NOTCH1-MYC-CD44 axis. As a proof of concept, degrading BRD4 with proteolysis targeting chimera (PROTAC) ARV-825, prolonged the survival of mice in Notch1 mutated patient-derived xenograft (PDX) and genetic …

The Microrna-183/96/182 Cluster Inhibits Lung Cancer Progression And Metastasis By Inducing An Interleukin-2-Mediated Antitumor Cd8+ Cytotoxic T-Cell Response, Samrat T Kundu, B Leticia Rodriguez, Laura A Gibson, Amanda N Warner, Mabel G Perez, Rakhee Bajaj, Jared J Fradette, Caleb A Class, Luisa M Solis, Frank R Rojas Alvarez, Ignacio I Wistuba, Lixia Diao, Fengju Chen, Mohit Sachdeva, Jing Wang, David G Kirsch, Chad J Creighton, Don L Gibbons

Faculty, Staff and Student Publications

Here, Kundu et al. investigated the role of the microRNA-183/96/182 cluster (m96cl) in lung cancer and used a novel conditional m96cl mouse to establish that loss of m96cl accelerated the growth of K-Ras mutant autochthonous lung adenocarcinomas. Overall, the authors identified a novel mechanistic role of the m96cl in the suppression of lung cancer growth and metastasis by inducing an IL2-mediated systemic CD8+ CTL immune response.

Bisphenol A Exposure Induces Sensory Processing Deficits In Larval Zebrafish During Neurodevelopment, Courtney Scaramella, Joseph B Alzagatiti, Christopher Creighton, Samandeep Mankatala, Fernando Licea, Gabriel M Winter, Jasmine Emtage, Joseph R Wisnieski, Luis Salazar, Anjum Hussain, Faith M Lee, Asma Mammootty, Niyaza Mammootty, Andrew Aldujaili, Kristine A Runnberg, Daniela Hernandez, Trevor Zimmerman-Thompson, Rikhil Makwana, Julien Rouvere, Zahra Tahmasebi, Gohar Zavradyan, Christopher S Campbell, Meghna Komaranchath, Javier Carmona, Jennifer Trevitt, David Glanzman, Adam C Roberts

2020-Current year OA Pubs

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Functional Analysis Of A Novel De Novo Variant In Ppp5c Associated With Microcephaly, Seizures, And Developmental Delay, Sara M Fielder, Jill A Rosenfeld, Lindsay C Burrage, Lisa Emrick, Seema Lalani, Ruben Attali, Joshua N Bembenek, Hieu Hoang, Dustin Baldridge, Gary A Silverman, Undiagnosed Diseases Network, Tim Schedl, Stephen C Pak

2020-Current year OA Pubs

We describe a proband evaluated through the Undiagnosed Diseases Network (UDN) who presented with microcephaly, developmental delay, and refractory epilepsy with a de novo p.Ala47Thr missense variant in the protein phosphatase gene, PPP5C. This gene has not previously been associated with a Mendelian disease, and based on the population database, gnomAD, the gene has a low tolerance for loss-of-function variants (pLI = 1, o/e = 0.07). We functionally evaluated the PPP5C variant in C. elegans by knocking the variant into the orthologous gene, pph-5, at the corresponding residue, Ala48Thr. We employed assays in three different biological processes where pph-5 was …

Heterozygous Frameshift Variants In Hnrnpa2b1 Cause Early-Onset Oculopharyngeal Muscular Dystrophy, Hong Joo Kim, Payam Mohassel, Sandra Donkervoort, Lin Guo, Kevin O'Donovan, Maura Coughlin, Xaviere Lornage, Nicola Foulds, Simon R Hammans, A Reghan Foley, Charlotte M Fare, Alice F Ford, Masashi Ogasawara, Aki Sato, Aritoshi Iida, Pinki Munot, Gautam Ambegaonkar, Rahul Phadke, Dominic G O'Donovan, Rebecca Buchert, Mona Grimmel, Ana Töpf, Irina T Zaharieva, Lauren Brady, Ying Hu, Thomas E Lloyd, Andrea Klein, Maja Steinlin, Alice Kuster, Sandra Mercier, Pascale Marcorelles, Yann Péréon, Emmanuelle Fleurence, Adnan Manzur, Sarah Ennis, Rosanna Upstill-Goddard, Luca Bello, Cinzia Bertolin, Elena Pegoraro, Leonardo Salviati, Courtney E French, Andriy Shatillo, F Lucy Raymond, Tobias B Haack, Susana Quijano-Roy, Johann Böhm, Isabelle Nelson, Tanya Stojkovic, Teresinha Evangelista, Volker Straub, Norma B Romero, Jocelyn Laporte, Francesco Muntoni, Ichizo Nishino, Mark A Tarnopolsky, James Shorter, Carsten G Bönnemann, J Paul Taylor

Department of Biochemistry and Molecular Biology Faculty Papers

Missense variants in RNA-binding proteins (RBPs) underlie a spectrum of disease phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, and inclusion body myopathy. Here, we present ten independent families with a severe, progressive muscular dystrophy, reminiscent of oculopharyngeal muscular dystrophy (OPMD) but of much earlier onset, caused by heterozygous frameshift variants in the RBP hnRNPA2/B1. All disease-causing frameshift mutations abolish the native stop codon and extend the reading frame, creating novel transcripts that escape nonsense-mediated decay and are translated to produce hnRNPA2/B1 protein with the same neomorphic C-terminal sequence. In contrast to previously reported disease-causing missense variants in HNRNPA2B1, these frameshift …

Christian Asceticism, David Allen Osb

Obsculta

The experience of the desert and wildlife was one of the hallmarks of early Christian monasticism. This paper offers a few vignettes about how animals and the natural world influenced the spirituality and writing of the ascetic life of early Christian monastics.

Vaccine Protection Against The Sars-Cov-2 Omicron Variant In Macaques, Abishek Chandrashekar, Adrianus C. M. Boon, Et Al.

2020-Current year OA Pubs

The rapid spread of the SARS-CoV-2 Omicron (B.1.1.529) variant, including in highly vaccinated populations, has raised important questions about the efficacy of current vaccines. In this study, we show that the mRNA-based BNT162b2 vaccine and the adenovirus-vector-based Ad26.COV2.S vaccine provide robust protection against high-dose challenge with the SARS-CoV-2 Omicron variant in cynomolgus macaques. We vaccinated 30 macaques with homologous and heterologous prime-boost regimens with BNT162b2 and Ad26.COV2.S. Following Omicron challenge, vaccinated macaques demonstrated rapid control of virus in bronchoalveolar lavage, and most vaccinated animals also controlled virus in nasal swabs. However, 4 vaccinated animals that had moderate Omicron-neutralizing antibody titers …

Targeting Cd123 In Blastic Plasmacytoid Dendritic Cell Neoplasm Using Allogeneic Anti-Cd123 Car T Cells, Tianyu Cai, Agnès Gouble, Kathryn L Black, Anna Skwarska, Ammar S Naqvi, Deanne Taylor, Ming Zhao, Qi Yuan, Mayumi Sugita, Qi Zhang, Roman Galetto, Stéphanie Filipe, Antonio Cavazos, Lina Han, Vinitha Kuruvilla, Helen Ma, Connie Weng, Chang-Gong Liu, Xiuping Liu, Sergej Konoplev, Jun Gu, Guilin Tang, Xiaoping Su, Gheath Al-Atrash, Stefan Ciurea, Sattva S Neelapu, Andrew A Lane, Hagop Kantarjian, Monica L Guzman, Naveen Pemmaraju, Julianne Smith, Andrei Thomas-Tikhonenko, Marina Konopleva

Faculty, Staff and Student Publications

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with poor outcomes with conventional therapy. Nearly 100% of BPDCNs overexpress interleukin 3 receptor subunit alpha (CD123). Given that CD123 is differentially expressed on the surface of BPDCN cells, it has emerged as an attractive therapeutic target. UCART123 is an investigational product consisting of allogeneic T cells expressing an anti-CD123 chimeric antigen receptor (CAR), edited with TALEN

Future Of Biomedical, Agricultural, And Biological Systems Research Using Domesticated Animals, Thomas E Spencer, Kevin D Wells, Kiho Lee, Bhanu P Telugu, Peter J Hansen, Frank F Bartol, Leann Blomberg, Lawrence B Schook, Harry Dawson, Joan K Lunney, John P Driver, Teresa A Davis, Sharon M Donovan, Ryan N Dilger, Linda J Saif, Adam Moeser, Jodi L Mcgill, George Smith, James J Ireland

Children’s Nutrition Research Center Staff Publications

Increased knowledge of reproduction and health of domesticated animals is integral to sustain and improve global competitiveness of U.S. animal agriculture, understand and resolve complex animal and human diseases, and advance fundamental research in sciences that are critical to understanding mechanisms of action and identifying future targets for interventions. Historically, federal and state budgets have dwindled and funding for the United States Department of Agriculture (USDA) National Institute of Food and Agriculture (NIFA) competitive grants programs remained relatively stagnant from 1985 through 2010. This shortage in critical financial support for basic and applied research, coupled with the underappreciated knowledge of …

A Periplasmic Cinched Protein Is Required For Siderophore Secretion And Virulence Of Mycobacterium Tuberculosis., Lei Zhang, James E Kent, Meredith Whitaker, David C Young, Dominik Herrmann, Alexander E Aleshin, Ying-Hui Ko, Gino Cingolani, Jamil S Saad, D Branch Moody, Francesca M Marassi, Sabine Ehrt, Michael Niederweis

Department of Biochemistry and Molecular Biology Faculty Papers

Iron is essential for growth of Mycobacterium tuberculosis, the causative agent of tuberculosis. To acquire iron from the host, M. tuberculosis uses the siderophores called mycobactins and carboxymycobactins. Here, we show that the rv0455c gene is essential for M. tuberculosis to grow in low-iron medium and that secretion of both mycobactins and carboxymycobactins is drastically reduced in the rv0455c deletion mutant. Both water-soluble and membrane-anchored Rv0455c are functional in siderophore secretion, supporting an intracellular role. Lack of Rv0455c results in siderophore toxicity, a phenotype observed for other siderophore secretion mutants, and severely impairs replication of M. tuberculosis in mice, demonstrating …

Circadian Pacemaker Neurons Display Cophasic Rhythms In Basal Calcium Level And In Fast Calcium Fluctuations, Xitong Liang, Timothy E Holy, Paul H Taghert

Open Access Publications

SignificanceDaily rhythms in the molecular clock, in calcium, and in electrical activity all interact to support the functions of circadian pacemaker neurons. However, the regulatory mechanisms that unify these properties are not defined. Here, we utilize the cellular resolution of the

Antiviral Activity Of Olanexidine-Containing Hand Rub Against Human Noroviruses, Khalil Ettayebi, Wilhelm Salmen, Kaoru Imai, Akifumi Hagi, Frederick H Neill, Robert L Atmar, B V Venkataram Prasad, Mary K Estes

Faculty, Staff and Students Publications

Human norovirus (HuNoV) is the leading cause of epidemic and sporadic acute gastroenteritis worldwide. HuNoV transmission occurs predominantly by direct person-to-person contact, and its health burden is associated with poor hand hygiene and a lack of effective antiseptics and disinfectants. Specific therapies and methods to prevent and control HuNoV spread previously were difficult to evaluate because of the lack of a cell culture system to propagate infectious virus. This barrier has been overcome with the successful cultivation of HuNoV in nontransformed human intestinal enteroids (HIEs). Here, we report using the HIE cultivation system to evaluate the virucidal efficacy of an …

Silencing Alanine Transaminase 2 In Diabetic Liver Attenuates Hyperglycemia By Reducing Gluconeogenesis From Amino Acids, Michael R. Martino, Manuel Gutiérrez-Aguilar, Nicole K. H. Yiew, Andrew J. Lutkewitte, Jason M. Singer, Kyle S. Mccommis, Daniel Ferguson, Kim H. H. Liss, Jun Yoshino, M. Katie Renkemeyer, Gordon I. Smith, Kevin Cho, Justin A. Fletcher, Samuel Klein, Gary J. Patti, Shawn C. Burgess, Brian N. Finck

2020-Current year OA Pubs

Hepatic gluconeogenesis from amino acids contributes significantly to diabetic hyperglycemia, but the molecular mechanisms involved are incompletely understood. Alanine transaminases (ALT1 and ALT2) catalyze the interconversion of alanine and pyruvate, which is required for gluconeogenesis from alanine. We find that ALT2 is overexpressed in the liver of diet-induced obese and db/db mice and that the expression of the gene encoding ALT2 (GPT2) is downregulated following bariatric surgery in people with obesity. The increased hepatic expression of Gpt2 in db/db liver is mediated by activating transcription factor 4, an endoplasmic reticulum stress-activated transcription factor. Hepatocyte-specific knockout of Gpt2 attenuates incorporation of

Products Of Gut Microbial Toll/Interleukin-1 Receptor Domain Nadase Activities In Gnotobiotic Mice And Bangladeshi Children With Malnutrition, James S Weagley, Mark Zaydman, Siddarth Venkatesh, Yo Sasaki, Neha Damaraju, Alex Yenkin, William Buchser, Dmitry A Rodionov, Andrei Osterman, Tahmeed Ahmed, Michael J Barratt, Aaron Diantonio, Jeffrey Milbrandt, Jeffrey I Gordon

2020-Current year OA Pubs

Perturbed gut microbiome development has been linked to childhood malnutrition. Here, we characterize bacterial Toll/interleukin-1 receptor (TIR) protein domains that metabolize nicotinamide adenine dinucleotide (NAD), a co-enzyme with far-reaching effects on human physiology. A consortium of 26 human gut bacterial strains, representing the diversity of TIRs observed in the microbiome and the NAD hydrolase (NADase) activities of a subset of 152 bacterial TIRs assayed in vitro, was introduced into germ-free mice. Integrating mass spectrometry and microbial RNA sequencing (RNA-seq) with consortium membership manipulation disclosed that a variant of cyclic-ADPR (v-cADPR-x) is a specific product of TIR NADase activity and a …

Where's Baby Elephant, Amanda Morgan

Children's Book and Media Review

A baby elephant is somewhere near, but a lion family says she’s not with them. A shark and her young know she’s not under the sea. She is also not with a wolf and her cub. It is too cold for her to be with the penguin and her little chick. From one set of animals to another we go until we find the baby elephant with her mother.

From 1 To 10, Amanda Morgan

Children's Book and Media Review

From the bear’s one belly to the cat’s ten whiskers, all the animals have a number to teach, progressing from one to ten.

Duck, Duck, Moose, Amanda Morgan

Children's Book and Media Review

Goose is missing, so the girl enlists the help of Duck, Duck, and Moose to find their feathered friend. They take Tractor and search across the farm, asking for help from all the other animals. In their panic, they run into a lot of trouble and make quite a mess, and at the end of the day, they go home sad having not found Goose. Then the next morning, they are happily surprised to find out just where Goose had gone.

Migration: Incredible Animal Journeys, Jennifer Padgett

Children's Book and Media Review

Annually, a variety of species spanning the globe make amazing and courageous voyages. A humpback whale swims with its mother from the warm waters of the Pacific Ocean near Australia to the frigid coast of Antarctica. Some travel as many as 15,000 miles per year, more than any other creature on earth. Emperor penguins trek each year from their breeding grounds into the sea to search for fish. Globe skimmer dragonflies migrate from India to eastern Africa and back again, making them the farthest-traveling insect in the world. African elephants march from the dry lands of the Kalahari region to …

Not An Alphabet Book: The Case Of The Missing Cake, Amanda Morgan

Children's Book and Media Review

This alphabet book is going normally until the cake on letter C page is stolen. Bear, representing letter B, is determined to find the culprit, but he needs a little help from the readers. Bear leads the reader from page to page looking for clues. Bear thinks Fox might be the culprit, but Gingerbread Man testifies that Fox has changed since he took a bite out of him. Bear then wanders if it might be Octopus since, after all, his tentacles are all over the pages. As Bear questions more characters, the evidence piles up, and soon the perpetrator is …

Green Planet: Life In Our Woods And Forests, Jazmin Gomez

Children's Book and Media Review

Green Planet and its companion book, Blue Planet, are part of Moira Butterfield’s Colors of the World series. The book explains the anatomy and importance of trees, as they provide homes to more than half of the world’s plant and animal population. The introduction also gives examples of different types of extreme trees. Most of the book is dedicated to the wildlife found in Earth’s woods and forests. It covers a wide range of animals, from grizzly bears and pine martens to ground beetles and goliath bird-eating spiders. The last pages are dedicated to the many uses for wood, including …

Animals Go To War: From Dogs To Dolphins, Jennifer Haltli

Children's Book and Media Review

From heroic dogs and hunting house cats to unlikely creatures like pigeons, pigs, and camels, animals have turned the tides of battles and aided humans in dealing with the terrible aftermath. Working as fighters, transporters, messengers, detectors, searchers, rescuers, emotional supporters and spies, animals have served in wartime from Hannibal’s era to today’s war on terror. Babylonian reliefs pictured their exploits, ancient Greek historians chronicled their deeds, and modern European newspapers publish their photos. While exposing animals to wartime conditions is controversial, these beasts are often given military awards and are immortalized by the media and their handlers.

The Bear, The Piano, The Dog, And The Fiddle, Jazmin Gomez

Children's Book and Media Review

Hector enjoys playing his fiddle on the streets of New Orleans with his canine friend, Hugo, by his side. When he becomes disheartened, he puts his fiddle away for good. Hector distracts himself with other hobbies and has no idea that Hugo has been spending months learning to play the fiddle. Hector hears him one night and sees how much Hugo loves playing. News of the fiddle-playing dog spreads, and he is soon recruited by the famous piano-playing bear. As Hugo is leaving to tour with the band, Hector’s jealousy leads him to say hurtful things. When the band returns …

Reindolphins, Karen Abbott

Children's Book and Media Review

With all of the reindeer sick, Santa may have to cancel Christmas because he can't pull the sleigh by himself. Then a quick-thinking elf suggests finding another animal to substitute for the ailing deer. They hold tryouts, but problems with each animal eliminate them from the running. The smart little elf pulls Santa out to the ocean and suggests dolphins, who are only too happy to help because they can “splash away, splash away, splash away all!"

The Truth About Crocodiles, Amanda Morgan

Children's Book and Media Review

There are lots of interesting facts about crocodiles. Baby crocs make kitten noises, and some crocs lure birds in by putting sticks over their noses. The Truth about Crocodiles introduces readers to these facts and so much more as three crocs with personality travel through the illustrations, demonstrating their skills and unique traits. Each section provides a unique perspective. For example, on one page a little girl plans a birthday party with hatchlings to share information about crocs’ life cycles. Even a lizard and a turtle chime in along the way with a fact about their crocodilian cousins.

Sleep, Krista Alletto

Children's Book and Media Review

All animals sleep, but they don't all sleep the same way. This book teaches through words and pictures how different animals get their rest. Each page simply explains where or how a particular animal sleeps. For example, mice sleep in nests while "snails sleep in their shells." "Giraffes sleep standing up" and "sloths sleep upside down." At the end of the book, the author poses the question to readers, "Do you think animals dream?"

Don't Call Me Bear, Amanda Morgan

Children's Book and Media Review

Warren the Koala would like the whole world to know that he is not a bear. He is a marsupial, like kangaroos and possums. He doesn't eat fish or frighten hikers. He doesn't even live where bears do. He lives in Australia. There are no wild bears in Australia. Using diagrams and examples to demonstrate, Warren explains politely and eventually screams loudly in protest, but no matter what he tries, everyone still calls him bear.

Black Beauty, Taylor Bitton

Children's Book and Media Review

Black Beauty is a high bred horse, born and raised in the pastures of Victorian England. His first owners have been very kind and gentle, so Beauty has a very agreeable disposition. As soon as he is old enough, Beauty is sold to new owners. Eventually these owners decide to move, so he is sold again. Years pass, and Beauty is owned by kind and cruel people alike. He experiences the freedom of country pastures and the difficulties of city life. Throughout it all, Beauty makes new friends and works hard and please the people he serves. Though he is …

Vernon Is On His Way, Lindsey Smith

Children's Book and Media Review

Vernon is on His Way tells the three adventure stories of friends Vernon, Porcupine, and Skunk as they discover the world. In the first story, the friends plan to go fishing. Although Porcupine worries about not knowing how to fish, it becomes apparent that neither Skunk nor Vernon knows either, and they all have a good time anyway. In the last story, Vernon is missing his friend Bird, so Porcupine and Skunk determine they will cheer him up.

Mr. Scruff, Jessica Mellor

Children's Book and Media Review

Minnie belongs to Vinnie, just like every dog belongs to an owner who looks like them. But there isn’t anyone for Mr. Scruff. That is, until he discovers Jim, who seems to like Mr. Scruff and decides to take him. But when Jim finds Mr. Gruff, they realize that Mr. Gruff and Jim may have found the wrong dogs.