Digital Commons Network^™

Dose-Dependent Effects Of Dnmt3a In An Inducible Murine Model Of Krasg12d-Driven Leukemia, Jason H Rogers, Allison Rosen, Jaime M Reyes, Shamika Ketkar, Shannon E Conneely, Rohit Gupta, Luibin Yang, Matthew B Miller, Geraldo Medrano, Rogelio Aguilar, Nneka Uchenda, Margaret A Goodell, Rachel E Rau

Children’s Nutrition Research Center Staff Publications

DNMT3A mutations are frequently found in clonal hematopoiesis and a variety of hematologic malignancies including acute myeloid leukemia (AML). An assortment of mouse models have been engineered to explore the tumorigenic potential and malignant lineage bias due to loss of function of DNMT3A in consort with commonly co-mutated genes in myeloid malignancies such as Flt3, Nras, Kras, and c-Kit. We employed several tamoxifen-inducible Cre-ER^T2 murine model systems to study the effects of constitutively active Kras^G12D-driven myeloid leukemia (Kras) development together with heterozygous (3aHet) or homozygous Dnmt3a deletion (3aKO). Due to the rapid generation of …

Inhibition Of Cathepsin S In Autoimmune Cd25ko Mouse Improves Sjögren Disease-Like Lacrimal Gland Pathology, Kaitlin K Scholand, Jeremias Galletti, Wolfgang Haap, Tiago Santos-Ferreira, Christoph Ullmer, Cintia S De Paiva

Faculty, Staff and Students Publications

PURPOSE: CD25KO mice are a model of Sjögren disease (SjD) driven by autoreactive T cells. Cathepsin S (CTSS) is a protease crucial for major histocompatibility complex class II presentation that primes T cells. We investigated if a diet containing CTSS inhibitor would improve autoimmune signs in CD25KO mice.

METHODS: Four-week female CD25KO mice were randomly chosen to receive chow containing a CTSS inhibitor (R05461111, 262.5 mg/kg chow) or standard chow for 4 weeks. Cornea sensitivity was measured. Inflammatory score was assessed in lacrimal gland (LG) histologic sections. Flow cytometry of LG and ocular draining lymph nodes (dLNs) investigated expression of …

Genetic Deletion Of Galectin-3 Inhibits Pancreatic Cancer Progression And Enhances The Efficacy Of Immunotherapy, Daowei Yang, Xinlei Sun, Rohan Moniruzzaman, Hua Wang, Citu Citu, Zhongming Zhao, Ignacio I Wistuba, Huamin Wang, Anirban Maitra, Yang Chen

Faculty, Staff and Student Publications

Background & aims: Pancreatic ductal adenocarcinoma (PDAC) has a desmoplastic tumor stroma and immunosuppressive microenvironment. Galectin-3 (GAL3) is enriched in PDAC, highly expressed by cancer cells and myeloid cells. However, the functional roles of GAL3 in the PDAC microenvironment remain elusive.

Methods: We generated a novel transgenic mouse model (LSL-KrasG12D/+;Trp53loxP/loxP;Pdx1-Cre;Lgals3-/- [KPPC;Lgals3-/-]) that allows the genetic depletion of GAL3 from both cancer cells and myeloid cells in spontaneous PDAC formation. Single-cell RNA-sequencing analysis was used to identify the alterations in the tumor microenvironment upon GAL3 depletion. We investigated both the cancer cell-intrinsic function and immunosuppressive function of GAL3. We also evaluated …

Learning Curve For Endoscopic Submucosal Dissection (Esd) In The United States: Large, Untutored, Single-Operator Experience, Mai A Khalaf, Fares Ayoub, Kristen A Staggers, Johanna W El-Haj, Salmaan Jawaid, Mohamed O Othman

Faculty, Staff and Students Publications

Background and study aims Endoscopic submucosal dissection (ESD) allows removal of tumors en-bloc. Western adoption of ESD has been hindered by its steep learning curve. Western data regarding ESD learning curve are limited. We analyzed the learning curve of a single endoscopist at a tertiary referral center in the United States.

Patients and methods All consecutive ESDs performed by a single endoscopist at a tertiary referral center in the United States from 2015 through 2022 were identified. Descriptive statistics and CUSUM analysis were used to describe the learning curve for en-bloc, R0 resection, and resection speed.\

Results In our study, …

T-Bet Regulates Ion Channels And Transporters And Induces Apoptosis In Intestinal Epithelial Cells, Lang Chen, Hongwei Yi, Qingtian Li, Tianhao Duan, Xin Liu, Linfeng Li, Helen Y Wang, Changsheng Xing, Rong-Fu Wang

Faculty, Staff and Students Publications

T-bet, encoded by TBX21, is extensively expressed across various immune cell types, and orchestrates critical functions in their development, survival, and physiological activities. However, the role of T-bet in non-immune compartments, notably the epithelial cells, remains obscure. Herein, a Tet-O-T-bet transgenic mouse strain is generated for doxycycline-inducible T-bet expression in adult animals. Unexpectedly, ubiquitous T-bet overexpression causes acute diarrhea, intestinal damage, and rapid mortality. Cell-type-specific analyses reveal that T-bet-driven pathology is not attributable to its overexpression in CD4

Lethal Phenotypes In Mendelian Disorders, Pilar Cacheiro, Samantha Lawson, Ignatia B Van Den Veyver, Gabriel Marengo, David Zocche, Stephen A Murray, Michael Duyzend, Peter N Robinson, Damian Smedley

Center for Medical Ethics and Health Policy Staff Publications

Purpose: Existing resources that characterize the essentiality status of genes are based on either proliferation assessment in human cell lines, viability evaluation in mouse knockouts, or constraint metrics derived from human population sequencing studies. Several repositories document phenotypic annotations for rare disorders; however, there is a lack of comprehensive reporting on lethal phenotypes.

Methods: We queried Online Mendelian Inheritance in Man for terms related to lethality and classified all Mendelian genes according to the earliest age of death recorded for the associated disorders, from prenatal death to no reports of premature death. We characterized the genes across these lethality categories, …

Acute Kidney Injury In Patients With Cirrhosis: Acute Disease Quality Initiative (Adqi) And International Club Of Ascites (Ica) Joint Multidisciplinary Consensus Meeting, Mitra K Nadim, John A Kellum, Lui Forni, Claire Francoz, Sumeet K Asrani, Marlies Ostermann, Andrew S Allegretti, Javier A Neyra, Jody C Olson, Salvatore Piano, Lisa B Vanwagner, Elizabeth C Verna, Ayse Akcan-Arikan, Paolo Angeli, Justin M Belcher, Scott W Biggins, Akash Deep, Guadalupe Garcia-Tsao, Yuri S Genyk, Pere Gines, Patrick S Kamath, Sandra L Kane-Gill, Manish Kaushik, Nuttha Lumlertgul, Etienne Macedo, Rakhi Maiwall, Sebastian Marciano, Raimund H Pichler, Claudio Ronco, Puneeta Tandon, Juan-Carlos Q Velez, Ravindra L Mehta, François Durand

Faculty, Staff and Students Publications

Patients with cirrhosis are prone to developing acute kidney injury (AKI), a complication associated with a markedly increased in-hospital morbidity and mortality, along with a risk of progression to chronic kidney disease. Whereas patients with cirrhosis are at increased risk of developing any phenotype of AKI, hepatorenal syndrome (HRS), a specific form of AKI (HRS-AKI) in patients with advanced cirrhosis and ascites, carries an especially high mortality risk. Early recognition of HRS-AKI is crucial since administration of splanchnic vasoconstrictors may reverse the AKI and serve as a bridge to liver transplantation, the only curative option. In 2023, a joint meeting …

The Multifaceted Life Of Macrophages In White Adipose Tissue: Immune Shift Couples With Metabolic Switch, Qun Wang, Sean M Hartig, Christie M Ballantyne, Huaizhu Wu

Faculty, Staff and Students Publications

White adipose tissue (WAT) is a vital endocrine organ that regulates energy balance and metabolic homeostasis. In addition to fat cells, WAT harbors macrophages with distinct phenotypes that play crucial roles in immunity and metabolism. Nutrient demands cause macrophages to accumulate in WAT niches, where they remodel the microenvironment and produce beneficial or detrimental effects on systemic metabolism. Given the abundance of macrophages in WAT, this review summarizes the heterogeneity of WAT macrophages in physiological and pathological conditions, including their alterations in quantity, phenotypes, characteristics, and functions during WAT growth and development, as well as healthy or unhealthy expansion. We …

Mechanisms Of Gelofusine Protection In An In Vitro Model Of Polymyxin B-Associated Renal Injury, Cole S Hudson, Anirban Roy, Qingtian Li, Aniket S Joshi, Taijun Yin, Ashok Kumar, David Sheikh-Hamad, Vincent H Tam

Faculty, Staff and Students Publications

Polymyxins are a last-resort treatment option for multidrug-resistant gram-negative bacterial infections, but they are associated with nephrotoxicity. Gelofusine was previously shown to reduce polymyxin-associated kidney injury in an animal model. However, the mechanism(s) of renal protection has not been fully elucidated. Here, we report the use of a cell culture model to provide insights into the mechanisms of renal protection. Murine epithelial proximal tubular cells were exposed to polymyxin B. Cell viability, lactate dehydrogenase (LDH) release, polymyxin B uptake, mitochondrial superoxide production, nuclear morphology, and apoptosis activation were evaluated with or without concomitant gelofusine. A megalin knockout cell line was …

Exome Sequencing Identifies Novel Genes Underlying Primary Congenital Glaucoma In The National Birth Defects Prevention Study, Elizabeth E Blue, Kristin J Moore, Kari E North, Tania A Desrosiers, Suzan L Carmichael, Janson J White, Jessica X Chong, Michael J Bamshad, Mary M Jenkins, Lynn M Almli, Lawrence C Brody, Sharon F Freedman, Jennita Reefhuis, Paul A Romitti, Gary M Shaw, Martha Werler, Denise M Kay, Marilyn L Browne, Marcia L Feldkamp, Richard H Finnell, Wendy N Nembhard, Faith Pangilinan, Andrew F Olshan, National Institutes Of Health Intramural Sequencing Center, University Of Washington Center For Mendelian Genomics, National Birth Defects Prevention Study

Faculty, Staff and Students Publications

Background: Primary congenital glaucoma (PCG) affects approximately 1 in 10,000 live born infants in the United States (U.S.). PCG has a autosomal recessive inheritance pattern, and variable expressivity and reduced penetrance have been reported. Likely causal variants in the most commonly mutated gene, CYP1B1, are less prevalent in the U.S., suggesting that alternative genes may contribute to the condition. This study utilized exome sequencing to investigate the genetic architecture of PCG in the U.S. and to identify novel genes and variants.

Methods: We studied 37 family trios where infants had PCG and were part of the National Birth Defects Prevention …

Comparative Analysis Of Atherogenic Lipoproteins L5 And Lp(A) In Atherosclerotic Cardiovascular Disease, Omer Akyol, Chao-Yuh Yang, Darren G Woodside, Huan-Hsing Chiang, Chu-Huang Chen, Antonio M Gotto

Faculty, Staff and Students Publications

Purpose of review: Low-density lipoprotein (LDL) poses a risk for atherosclerotic cardiovascular disease (ASCVD). As LDL comprises various subtypes differing in charge, density, and size, understanding their specific impact on ASCVD is crucial. Two highly atherogenic LDL subtypes-electronegative LDL (L5) and Lp(a)-induce vascular cell apoptosis and atherosclerotic changes independent of plasma cholesterol levels, and their mechanisms warrant further investigation. Here, we have compared the roles of L5 and Lp(a) in the development of ASCVD.

Recent findings: Lp(a) tends to accumulate in artery walls, promoting plaque formation and potentially triggering atherosclerosis progression through prothrombotic or antifibrinolytic effects. High Lp(a) levels correlate …

Artificial Intelligence To Classify Acquired Intestinal Injury In Preterm Neonates-A New Perspective, Alain Cuna, Muralidhar H Premkumar, Venkatesh Sampath

Faculty, Staff and Students Publications

No abstract provided.

Dna-Delivered Monoclonal Antibodies Targeting The P53 R175h Mutant Epitope Inhibit Tumor Development In Mice, Dafei Chai, Xu Wang, Praveen Neeli, Shan Zhou, Xingfang Yu, Kanaga Sabapathy, Yong Li

Faculty, Staff and Students Publications

The tumor suppressor p53 is the most common mutated gene in cancer, with the R175H as the most frequent p53 missense mutant. However, there are currently no approved targeted therapies or immunotherapies against mutant p53. Here, we characterized and investigated a monoclonal antibody (mAb) that recognizes the mutant p53-R175H for its affinity, specificity, and activity against tumor cells in vitro. We then delivered DNA plasmids expressing the anti-R175H mAb or a bispecific antibody (BsAb) into mice to evaluate their therapeutic effects. Our results showed that the anti-R175H mAb specifically bound to the p53-R175H antigen with a high affinity and …

Genome-Wide Association Study Identifies High-Impact Susceptibility Loci For Hcc In North America, Manal M Hassan, Donghui Li, Younghun Han, Jinyoung Byun, Rikita I Hatia, Erping Long, Jiyeon Choi, Robin Kate Kelley, Sean P Cleary, Anna S Lok, Paige Bracci, Jennifer B Permuth, Roxana Bucur, Jian-Min Yuan, Amit G Singal, Prasun K Jalal, R Mark Ghobrial, Regina M Santella, Yuko Kono, Dimpy P Shah, Mindie H Nguyen, Geoffrey Liu, Neehar D Parikh, Richard Kim, Hui-Chen Wu, Hashem El-Serag, Ping Chang, Yanan Li, Yun Shin Chun, Sunyoung S Lee, Jian Gu, Ernest Hawk, Ryan Sun, Chad Huff, Asif Rashid, Hesham M Amin, Laura Beretta, Robert A Wolff, Samuel O Antwi, Yehuda Patt, Lu-Yu Hwang, Alison P Klein, Karen Zhang, Mikayla A Schmidt, Donna L White, John A Goss, Saira A Khaderi, Jorge A Marrero, Francisco G Cigarroa, Pankil K Shah, Ahmed O Kaseb, Lewis R Roberts, Christopher I Amos

Faculty, Staff and Student Publications

BACKGROUND AND AIMS: Despite the substantial impact of environmental factors, individuals with a family history of liver cancer have an increased risk for HCC. However, genetic factors have not been studied systematically by genome-wide approaches in large numbers of individuals from European descent populations (EDP).

APPROACH AND RESULTS: We conducted a 2-stage genome-wide association study (GWAS) on HCC not affected by HBV infections. A total of 1872 HCC cases and 2907 controls were included in the discovery stage, and 1200 HCC cases and 1832 controls in the validation. We analyzed the discovery and validation samples separately and then conducted a …

Epigenetic Activation Of Sox11 Is Associated With Recurrence And Progression Of Ductal Carcinoma In Situ To Invasive Breast Cancer, Warapen Treekitkarnmongkol, Vandna Shah, Kazuharu Kai, Hiroshi Katayama, Justin Wong, Farah A Ladha, Tristian Nguyen, Brian Menegaz, Wei Lu, Fei Yang, Barbara Mino, Ximing Tang, Mihai Gagea, Harsh Batra, Maria Gabriela Raso, Ignacio I Wistuba, Savitri Krishnamurthy, Sarah E Pinder, Elinor J Sawyer, Alastair M Thompson, Subrata Sen

Faculty, Staff and Student Publications

Background: Risk of recurrence and progression of ductal carcinoma in situ (DCIS) to invasive cancer remains uncertain, emphasizing the need for developing predictive biomarkers of aggressive DCIS.

Methods: Human cell lines and mouse models of disease progression were analyzed for candidate risk predictive biomarkers identified and validated in two independent DCIS cohorts.

Results: RNA profiling of normal mammary and DCIS tissues (n = 48) revealed that elevated SOX11 expression correlates with MKI67, EZH2, and DCIS recurrence score. The 21T human cell line model of DCIS progression to invasive cancer and two mouse models developing mammary intraepithelial neoplasia confirmed the findings. …

Subspecialty Choices Among Medicine-Pediatrics Graduates: Results From A Four-Year National Program Director Survey, Anoop Agrawal, Daniel Wells, Michael Kisielewski, Savita Misra, Benjamin Doolittle

Faculty, Staff and Students Publications

Background and objectives Dual-trained medicine-pediatrics physicians (med-peds) play an important role in the healthcare ecosystem. Little is known about the subspecialty choices of med-peds residency graduates. This study aims to characterize the subspecialty choices of med-peds residency graduates. Methods The Medicine-Pediatrics Program Directors Association (MPPDA) administers an annual survey to the program directors of all med-peds residency programs accredited by the Accreditation Council for Graduate Medical Education (ACGME). This project represents aggregate survey data from 2020-2023. Results The number of program directors responding to the survey ranged from 80.8% (63/78) to 85.7% (66/77; mean response rate: 82.8%). About 465 of …

Dyspneic And Pink, Christian Inchaustegui, Sarvari Yellapragada, Jack Badawy, Ameer Ahmed, Andrew White, Zaven Sargsyan

Faculty, Staff and Students Publications

No abstract provided.

Homozygous Missense Variants In Ykt6 Result In Loss Of Function And Are Associated With Developmental Delay, With Or Without Severe Infantile Liver Disease And Risk For Hepatocellular Carcinoma, Mengqi Ma, Mythily Ganapathi, Yiming Zheng, Kai-Li Tan, Oguz Kanca, Kevin E Bove, Norma Quintanilla, Sebnem O Sag, Sehime G Temel, Charles A Leduc, Amanda J Mcpartland, Elaine M Pereira, Yufeng Shen, Jacob Hagen, Christie P Thomas, Nhu Thao Nguyen Galván, Xueyang Pan, Shenzhao Lu, Jill A Rosenfeld, Daniel G Calame, Michael F Wangler, James R Lupski, Davut Pehlivan, Paula M Hertel, Wendy K Chung, Hugo J Bellen

Faculty, Staff and Students Publications

PURPOSE: YKT6 plays important roles in multiple intracellular vesicle trafficking events but has not been associated with Mendelian diseases.

METHODS: We report 3 unrelated individuals with rare homozygous missense variants in YKT6 who exhibited neurological disease with or without a progressive infantile liver disease. We modeled the variants in Drosophila. We generated wild-type and variant genomic rescue constructs of the fly ortholog dYkt6 and compared their ability in rescuing the loss-of-function phenotypes in mutant flies. We also generated a dYkt6

RESULTS: Two individuals are homozygous for YKT6 [NM_006555.3:c.554A>G p.(Tyr185Cys)] and exhibited normal prenatal course followed by failure to thrive, …

Aging Atlas Reveals Cell-Type-Specific Effects Of Pro-Longevity Strategies, Shihong Max Gao, Yanyan Qi, Qinghao Zhang, Youchen Guan, Yi-Tang Lee, Lang Ding, Lihua Wang, Aaron S Mohammed, Hongjie Li, Yusi Fu, Meng C Wang

Faculty, Staff and Students Publications

Organismal aging involves functional declines in both somatic and reproductive tissues. Multiple strategies have been discovered to extend lifespan across species. However, how age-related molecular changes differ among various tissues and how those lifespan-extending strategies slow tissue aging in distinct manners remain unclear. Here we generated the transcriptomic Cell Atlas of Worm Aging (CAWA, http://mengwanglab.org/atlas ) of wild-type and long-lived strains. We discovered cell-specific, age-related molecular and functional signatures across all somatic and germ cell types. We developed transcriptomic aging clocks for different tissues and quantitatively determined how three different pro-longevity strategies slow tissue aging distinctively. Furthermore, through genome-wide profiling …

Cell-Type Resolved Transcriptomic Approaches For Dissecting Selective Vulnerability In Neurodegeneration, Caleb A Wood, Nicholas M Tran

Faculty, Staff and Students Publications

No abstract provided.

Origins Of Cancer: Ain’T It Just Mature Cells Misbehaving?, Charles J Cho, Jeffrey W Brown, Jason C Mills

Faculty, Staff and Students Publications

A pervasive view is that undifferentiated stem cells are alone responsible for generating all other cells and are the origins of cancer. However, emerging evidence demonstrates fully differentiated cells are plastic, can be coaxed to proliferate, and also play essential roles in tissue maintenance, regeneration, and tumorigenesis. Here, we review the mechanisms governing how differentiated cells become cancer cells. First, we examine the unique characteristics of differentiated cell division, focusing on why differentiated cells are more susceptible than stem cells to accumulating mutations. Next, we investigate why the evolution of multicellularity in animals likely required plastic differentiated cells that maintain …

Nfatc1 Is Required For Vitamin D- And Phosphate-Mediated Regulation Of Osteocyte Lacuno-Canalicular Remodeling, Supriya Jagga, Ashleigh Hughes, Niusha Manoochehri Arash, Melissa Sorsby, Daniel J Brooks, Paola Divieti Pajevic, Eva S Liu

Staff and Researcher Publications

Osteocytes are embedded in lacunae and connected by canaliculi (lacuno-canalicular network, LCN). Bones from mice with X-linked hypophosphatemia (Hyp), which have impaired production of 1,25 dihydroxyvitamin D (1,25D) and hypophosphatemia, have abnormal LCN structure that is improved by treatment with 1,25D or an anti-FGF23 targeting antibody, supporting roles for 1,25D and phosphate in regulating LCN remodeling. Bones from mice lacking the vitamin D receptor (VDR) in osteocytes (Vdrf/f;Dmp1Cre+) and mice lacking the sodium phosphate transporter 2a (Npt2aKO), which have low serum phosphate with high serum 1,25D, have impaired LCN organization, demonstrating that osteocyte-specific actions of 1,25D and hypophosphatemia regulate LCN …

A Klf2-Bmper-Smad1/5 Checkpoint Regulates High Fluid Shear Stress-Mediated Artery Remodeling, Hanqiang Deng, Jiasheng Zhang, Yewei Wang, Divyesh Joshi, Xinchun Pi, Sarah De Val, Martin A Schwartz

Faculty, Staff and Students Publications

Vascular remodeling to match arterial diameter to tissue requirements commonly fails in ischemic disease. Endothelial cells sense fluid shear stress (FSS) from blood flow to maintain FSS within a narrow range in healthy vessels. Thus, high FSS induces vessel outward remodeling, but mechanisms are poorly understood. We previously reported that Smad1/5 is maximally activated at physiological FSS. Smad1/5 limits Akt activation, suggesting that inhibiting Smad1/5 may facilitate outward remodeling. Here we report that high FSS suppresses Smad1/5 by elevating KLF2, which induces the bone morphogenetic protein (BMP) pathway inhibitor, BMP-binding endothelial regulator (BMPER), thereby de-inhibiting Akt. In mice, surgically induced …

The Effect Of Adamts13 On Graft-Versus-Host Disease, Dan Li, Min Soon Cho, Ricardo Gonzalez-Delgado, Xiaowen Liang, Jing-Fei Dong, Miguel A Cruz, Qing Ma, Vahid Afshar-Kharghan

Faculty, Staff and Student Publications

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) can potentially cure malignant blood disorders and benign conditions such as haemoglobinopathies and immunologic diseases. However, allo-HSCT is associated with significant complications. The most common and debilitating among them is graft-versus-host disease (GVHD). In GVHD, donor-derived T cells mount an alloimmune response against the recipient. The alloimmune response involves several steps, including recognition of recipient antigens, activation and proliferation of T cells in secondary lymphoid organs, and homing into GVHD-targeted organs. Adhesion molecules on T cells and endothelial cells mediate homing of T cells into lymphoid and non-lymphoid tissues. In this study, we showed …

Clinicopathologic Dissociation: Robust Lafora Body Accumulation In Malin Ko Mice Without Observable Changes In Home-Cage Behavior, Vaishnav Krishnan, Jun Wu, Arindam Ghosh Mazumder, Jessica L Kamen, Catharina Schirmer, Nandani Adhyapak, John Samuel Bass, Samuel C Lee, Atul Maheshwari, Gemma Molinaro, Jay R Gibson, Kimberly M Huber, Berge A Minassian

Faculty, Staff and Students Publications

Lafora disease (LD) is a syndrome of progressive myoclonic epilepsy and cumulative neurocognitive deterioration caused by recessively inherited genetic lesions of EPM2A (laforin) or NHLRC1 (malin). Neuropsychiatric symptomatology in LD is thought to be directly downstream of neuronal and astrocytic polyglucosan aggregates, termed Lafora bodies (LBs), which faithfully accumulate in an age-dependent manner in all mouse models of LD. In this study, we applied home-cage monitoring to examine the extent of neurobehavioral deterioration in a model of malin-deficient LD as a means to identify robust preclinical endpoints that may guide the selection of novel genetic treatments. At 6 weeks, ∼6-7 …

Effects Of Age On Lacrimal Gland Bioactive Lipids, Brandon Ebright, Zhiyuan Yu, Priyal Dave, Dante Dikeman, Sarah Hamm-Alvarez, Cintia S De Paiva, Stan Louie

Faculty, Staff and Students Publications

Purpose: Polyunsaturated fatty acids (PUFA) are a source of bioactive lipids regulating inflammation and its resolution.

Methods: Changes in PUFA metabolism were compared between lacrimal glands (LGs) from young and aged C57BL/6 J mice using a targeted lipidomics assay, as was the gene expression of enzymes involved in the metabolism of these lipids.

Results: Global reduction in PUFAs and their metabolites was observed in aged LGs compared to young controls, averaging between 25 and 66 % across all analytes. ꞷ-6 arachidonic acid (AA) metabolites were all reduced in aged LGs, where the changes in prostaglandin E2 (PGE2) and lipoxin A4 …

Metabolomics Analysis Reveals Metabolite Diversity Of The Rare Cliff Plant Oresitrophe Rupifraga Unge, Hao Wang, Jinjun Cao, Sheng Chang, Caifeng Yan, Guangming Zhang

Faculty, Staff and Student Publications

Oresitrophe is monotypic, with the only species, Oresitrophe rupifraga Bunge, which is exclusive to China, having special growth and developmental traits due to its habitat. Furthermore, it has bright flowers and medicinal benefits. This study investigated the metabolites present in various tissues of Oresitrophe rupifraga Bunge. Using a widely targeted metabolomics approach, 1965 different metabolites were identified in Oresitrophe rupifraga Bunge. Based on principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA), the aboveground and underground metabolites of Oresitrophe rupifraga differed significantly. The comparison between bulblets and leaves revealed the differential expression of 461 metabolites, whereas the …

Kibra Anchoring The Action Of Pkmζ Maintains The Persistence Of Memory, Panayiotis Tsokas, Changchi Hsieh, Rafael E Flores-Obando, Matteo Bernabo, Andrew Tcherepanov, A Iván Hernández, Christian Thomas, Peter J Bergold, James E Cottrell, Joachim Kremerskothen, Harel Z Shouval, Karim Nader, André A Fenton, Todd C Sacktor

Faculty, Staff and Student Publications

How can short-lived molecules selectively maintain the potentiation of activated synapses to sustain long-term memory? Here, we find kidney and brain expressed adaptor protein (KIBRA), a postsynaptic scaffolding protein genetically linked to human memory performance, complexes with protein kinase Mzeta (PKMζ), anchoring the kinase's potentiating action to maintain late-phase long-term potentiation (late-LTP) at activated synapses. Two structurally distinct antagonists of KIBRA-PKMζ dimerization disrupt established late-LTP and long-term spatial memory, yet neither measurably affects basal synaptic transmission. Neither antagonist affects PKMζ-independent LTP or memory that are maintained by compensating PKCs in ζ-knockout mice; thus, both agents require PKMζ for their effect. …

Type I Conventional Dendritic Cells Facilitate Immunotherapy In Pancreatic Cancer, Krishnan K Mahadevan, Allison M Dyevoich, Yang Chen, Bingrui Li, Hikaru Sugimoto, Amari M Sockwell, Kathleen M Mcandrews, Lakshmi Kavitha Sthanam, Huamin Wang, Shabnam Shalapour, Stephanie S Watowich, Raghu Kalluri

Faculty, Staff and Student Publications

Inflammation and tissue damage associated with pancreatitis can precede or occur concurrently with pancreatic ductal adenocarcinoma (PDAC). We demonstrate that in PDAC coupled with pancreatitis (ptPDAC), antigen-presenting type I conventional dendritic cells (cDC1s) are specifically activated. Immune checkpoint blockade therapy (iCBT) leads to cytotoxic CD8+ T cell activation and elimination of ptPDAC with restoration of life span even upon PDAC rechallenge. Using PDAC antigen-loaded cDC1s as a vaccine, immunotherapy-resistant PDAC was rendered sensitive to iCBT with elimination of tumors. cDC1 vaccination coupled with iCBT identified specific CDR3 sequences in the tumor-infiltrating CD8+ T cells with potential therapeutic importance. This study …

Neural Circuits Expressing The Serotonin 2c Receptor Regulate Memory In Mice And Humans, Hesong Liu, Yang He, Hailan Liu, Bas Brouwers, Na Yin, Katherine Lawler, Julia M Keogh, Elana Henning, Dong-Kee Lee, Meng Yu, Longlong Tu, Nan Zhang, Kristine M Conde, Junying Han, Zili Yan, Nikolas A Scarcelli, Lan Liao, Jianming Xu, Qingchun Tong, Hui Zheng, Zheng Sun, Yongjie Yang, Chunmei Wang, Yanlin He, I Sadaf Farooqi, Yong Xu

Children’s Nutrition Research Center Staff Publications

Declined memory is a hallmark of Alzheimer’s disease (AD). Experiments in rodents and human postmortem studies suggest that serotonin (5-hydroxytryptamine, 5-HT) plays a role in memory, but the underlying mechanisms are unknown. Here, we investigate the role of 5-HT 2C receptor (5-HT2CR) in regulating memory. Transgenic mice expressing a humanized HTR2C mutation exhibit impaired plasticity of hippocampal ventral CA1 (vCA1) neurons and reduced memory. Further, 5-HT neurons project to and synapse onto vCA1 neurons. Disruption of 5-HT synthesis in vCA1-projecting neurons or deletion of 5-HT2CRs in the vCA1 impairs neural plasticity and memory. We show that a selective 5-HT2CR agonist, …