Digital Commons Network^™

Garlic-Derived Metabolite Activates Lkb1, Promotes Adipose Enampt Secretion, And Improves Age-Related Muscle Function Via Hypothalamic Signaling, Jun-Ichiro Suzuki, Kiyoshi Yoshioka, Masahiro Kurita, Takumi Sugimoto, Takahiro Eguchi, Naoki Ito, Aoi Kodama, Yasutomi Kamei, Masahiro Ohtani, Toshiaki Matsutomo, Shin-Ichiro Imai

2020-Current year OA Pubs

Garlic (Allium sativum L.) and its aged extract contain many bioactive compounds that can bring health benefits to humans. Among them, S-1-propenyl-L-cysteine (S1PC) has recently drawn significant attention in the field of nutriceutical research. However, the mechanism of its molecular action has remained poorly understood. Here, we show that S1PC significantly activates liver kinase B1 (LKB1) through enhancing its tertiary complex formation with STRAD and MO25, leading to stimulating the phosphorylation of a mammalian NAD

The Effect Of Bai1 Deficiency On Cell Survival During The Critical Period Of Retinal Development, Nicholas Mirmanesh

PCOM Biomedical Studies Student Scholarship

The postnatal retina undergoes further development during the critical period, during which excess neurons are culled, and synapses are refined to shape the mature retinal circuitry. Brain-specific angiogenesis inhibitor-1 (BAI1) has been implicated in synaptic development, phagocytosis, the regulation of angiogenesis, and inflammatory signaling, suggesting it may play an important role in retinal maturation. The goal of this project was to determine how BAI1 deficiency affects retinal cell survival and layer morphology during the critical period. Mice were divided into three genotype groups: BAI1 +/+ Wild Type (WT), +/- (Het), and -/- (KO). Apoptotic cells were quantified using TUNEL staining …

Lingo4 Coordinates Ilc3-Intrinsic Il-22 Production And Microbiota-Mediated Ilc3 Homeostasis, José L Fachi, Tihana Trsan, Cristiane Sécca, Sarah De Oliveira, Vinícius R Rodovalho, Patrick Fernandes Rodrigues, Wandy L Beatty, Raki Sudan, Shitong Wu, Bishan Bhattarai, Santosh K Panda, Marina Cella, Susan Gilfillan, Marco Colonna

2020-Current year OA Pubs

LINGO4 is a leucine-rich repeat and immunoglobulin-like domain-containing transmembrane protein encoded immediately adjacent to Rorc, the gene for RORγt, raising the possibility that it contributes to the biology of RORγt+ lymphocytes. However, its impact on these cells and resistance to enteric infections has remained unknown. Here, we identify LINGO4 as a critical regulator of group 3 innate lymphoid cells (ILC3s). Lingo4-/- ILC3s exhibit a profound, cell-intrinsic defect in IL-22 production linked to impaired STAT3 activation, mitochondrial dysfunction, elevated ROS, and increased apoptosis. In vivo, Lingo4 deficiency also drives a dysbiotic gut microbiota, resulting in an additional, microbiota-dependent loss of ILC3s. …

An Obligatory Role For Agrp Neurons In Maintaining Body Temperature During Time-Restricted Feeding, Cunjin Su, Jing Cai, Yuanzhong Xu, Benjamin R Arenkiel, Qingchun Tong

The Brown Foundation: Institute of Molecular Medicine

Homeotherms maintain a steady body temperature through thermoregulation, a process critical for survival during fasting, in which the brain has to defend energy-costly body temperature while reducing energy expenditure to conserve energy reserve; however, the neural basis for defending body temperature remains unclear. Here, we demonstrated that AgRP neuron lesion led to lethality during time-restricted feeding on chow but not on HFD, and caused no obvious impact on HFD-induced obesity or obesity-reducing responses to glucagon-like peptide-1 receptor agonism. The lesion disrupted adaptive feeding behaviors during time-restricted feeding and reduced motivational feeding on chow. Notably, the lethality was caused by hypothermia …

Identification Of A Persistent Ascaris-Derived Kalirin Epitope Associated With Chronic T Cell Activation In The Lung, Yifan Wu, Leroy Versteeg, Meng-Chih Wu, Jill E Weatherhead

Faculty, Staff and Students Publications

Ascariasis remains a dominant global health burden due to its vast prevalence and associated morbidity. The obligatory migration of Ascaris larvae through pulmonary tissue triggers intense type-2 inflammation which typically presents as acute allergic airway disease. Even after the parasite is eliminated, a single episode of larval migration can result in chronic lung damage and dysfunction, which may be driven by the long-term retention of helminth antigens in macrophages. However, the molecular identity of these retained antigens, and the mechanisms by which they sustain chronic T cell responses, remain unknown. In this study, we utilized immunopeptidomics to identify a retained …

Generation And Characterization Of Twist1 Acetyl-Mimic And Acetyl-Deficient Mouse Models, Mary Elmeniawi, Xiaobin Yu, Samuel Wen, Gunjan A Bhatia, Lan Liao, Jianming Xu, Walid D Fakhouri

Faculty, Staff and Students Publications

TWIST1 encodes a highly conserved basic helix–loop–helix transcription factor essential for embryonic development from Drosophila to humans. TWIST1 activity is regulated by post‐translational modifications, including phosphorylation during development and cancer metastasis. Recent cancer studies identified acetylation of lysines K73 and K76 as a novel regulatory modification that shifts TWIST1 from a repressive to an activating state during epithelial‐to‐mesenchymal transition (EMT). However, the developmental and in vivo functions of TWIST1 acetylation remain unknown. To investigate the physiological role, we generated the first acetyl‐deficient Twist1 K73,76R K73,76R and acetyl‐mimic Twist1 K73,76Q K73,76Q mouse models using CRISPR/Cas9‐mediated genome editing. Targeted sequencing confirmed substitutions, …

Non-Isolated Dandy-Walker Malformation: Exome Sequencing Efficacy And Phenotypic Expansions, Sarah Araji, Xiaonan Zhao, Jill A Rosenfeld, Seema R Lalani, Daryl A Scott

Faculty, Staff and Students Publications

Dandy-Walker malformation (DWM) is a rare congenital abnormality of the posterior fossa and the cerebellum and has an incidence of 1 in 10 000 to 30 000 births. Although DWM can present in isolation, it is often associated with other central nervous system (CNS) abnormalities or extra-CNS anomalies (DWM+). A molecular cause is not identified in the majority of individuals with DWM+. This is due, in part, to uncertainty regarding optimal testing strategies and an incomplete understanding of the genetic causes of DWM+. In this study, we analyzed clinical exome sequencing (cES) data from 91 individuals with DWM+ to determine …

Unbiased Niche Labeling Maps Immune-Excluded Niche In Bone Metastasis, Zhan Xu, Fengshuo Liu, Yunfeng Ding, Tianhong Pan, Yi-Hsuan Wu, Yujiao Han, Jun Liu, Igor L Bado, Weijie Zhang, Ling Wu, Yang Gao, Xiaoxin Hao, Liqun Yu, Xuan Li, David G Edwards, Hilda L Chan, Sergio Aguirre, Michael Warren Dieffenbach, Elina Chen, Siyue Wang, Yichao Shen, Dane Hoffman, Luis Becerra Dominguez, Charlotte Helena Rivas, Xiang Chen, Hai Wang, Yibin Kang, Zbigniew Gugala, Robert L Satcher, Xiang H-F Zhang

Faculty, Staff and Students Publications

Metastatic cancer cell fate is shaped by the local microenvironment niches. To unbiasedly define the cellular and molecular features of metastatic niches, we developed sortase A-based microenvironment niche tagging (SAMENT), which selectively labels cells encountered by cancer cells during metastasis. Applying SAMENT across multiple cancer models and target organs revealed shared niche features, including macrophage enrichment and T cell depletion, alongside marked organ-specific phenotype heterogeneity in niche macrophages. In bone, metastatic niches are enriched for macrophages expressing estrogen receptor alpha (ERα) with active ERα signaling. Conditional deletion of Esr1 in macrophages significantly impaired bone colonization by enabling T cell infiltration. …

Development Of A Second-Generation Rarα Selective Antagonist As An Orally Bioavailable, Effective, Safe, And Reversible Male Contraceptive, Rui Shi, Kristen John, Xuan Qin, Ehfazul Haque, Taimeng Liang, Narsihmulu Cheryala, Feng Li, Henry L Wong, Gunda I Georg

Faculty, Staff and Students Publications

We report the design and SAR studies of benzopyran-, benzofuran-, and benzothiophene-derived inhibitors of the retinoic acid receptor alpha (RARα) for male contraception. SAR studies identified critical features influencing activity, such as the optimal positioning of antagonism moieties and substituents, leading to the discovery of (S)-4-(5-(2,8-dimethyl-5-(p-tolyl)-2H-chromen-3-yl)-1H-pyrrol-2-yl)­benzoic acid (compound 23). Compound 23 is a highly potent RARα inhibitor (IC50 = 0.051 nM) with excellent selectivity (>1650-fold over RARβ and >1960-fold over RARγ) and ADMET properties. Compound 23 is orally bioavailable and reduces sperm counts in mice for a full male contraceptive effect …

Inflammaging In Aged Tissues Drives Remodeling Of The Cd8+ T Cell Compartment, Irina Shchukina, Carlos J Rodriguez-Hernandez, Heather S Ruiz, Maksim Kleverov, Rachel L Mintz, Katsutaka Mineura, Subhadra C Gunawardana, Sunnie Hsiung, Bishan Bhattarai, Veronika Vachova, Jan Kossl, Denis A Mogilenko, Rachael L Field, Tran H Nguyen, Quazim A Alayo, Christopher G Huckstep, Barbora Vander Wielen, Jonathan R Brestoff, Sheila A Stewart, David W Piston, Takeshi Egawa, Daniel Kreisel, Gwendalyn J Randolph, Maxim N Artyomov

2020-Current year OA Pubs

Aging strongly impacts CD8

Isg15 Negatively Regulates Ripk3-Mediated Cell Death And Viral Pathogenesis, Yi-Chieh Perng, Jessica M C Warsaw, Sachendra S Bais, Bradley E Hiller, Marissa C Locke, David J Morales-Heil, Chaoqun Li, Alissa R Young, Kristen J Monte, Robert E Schmidt, Douglas R Green, Yi-Nan Gong, Deborah J Lenschow

2020-Current year OA Pubs

Necroptosis, a form of programmed, inflammatory necrosis, plays an important role in viral-host defense and inflammation. The receptor-interacting protein kinase 3 (RIPK3)/mixed lineage kinase domain-like pseudokinase (MLKL) pathway mediates necroptosis. Yet, the mechanisms that control necroptosis to limit immunopathology are poorly understood. Here, we report that interferon-stimulated gene 15 (ISG15) negatively regulates RIPK3-mediated cell death, including necroptosis, and limits immunopathology during chikungunya virus (CHIKV) infection. ISG15-deficient mice infected with CHIKV display increased levels of necroptosis, resulting in elevated proinflammatory cytokine and chemokine production, leading to increased lethality. This dysregulated host response is fully prevented when MLKL or RIPK3 is ablated …

Acidic Extracellular Ph-Induced Pth Secretion In Male Mouse Parathyroids Is Ogr1-Dependent, Yanmei Yang, Mengcun Chen, Mingshu Cui, Elisabeth Lashbrooks, Bin Wang

Center for Translational Medicine Faculty Papers

The role of extracellular acidity in regulating PTH secretion in cultured mouse parathyroid glands (PTGs) has not been studied to date, largely because of the technical difficulty of isolating mouse PTGs. We hypothesized that acidic extracellular pH directly stimulates PTH secretion through activation of a proton-sensing receptor, specifically ovarian cancer G protein-coupled receptor 1 (OGR1, also known as GPR68). To test this, we developed a method to reliably identify and isolate PTGs from male mice by administering 5-aminolevulinic acid, which induced selective fluorescence in these glands. Using this model, we demonstrate that acidic extracellular pH significantly stimulates PTH secretion in …

Acidic Extracellular Ph-Induced Pth Secretion In Male Mouse Parathyroids Is Ogr1-Dependent, Yanmei Yang, Mengcun Chen, Mingshu Cui, Elisabeth Lashbrooks, Bin Wang

Center for Translational Medicine Faculty Papers

The role of extracellular acidity in regulating PTH secretion in cultured mouse parathyroid glands (PTGs) has not been studied to date, largely because of the technical difficulty of isolating mouse PTGs. We hypothesized that acidic extracellular pH directly stimulates PTH secretion through activation of a proton-sensing receptor, specifically ovarian cancer G protein-coupled receptor 1 (OGR1, also known as GPR68). To test this, we developed a method to reliably identify and isolate PTGs from male mice by administering 5-aminolevulinic acid, which induced selective fluorescence in these glands. Using this model, we demonstrate that acidic extracellular pH significantly stimulates PTH secretion in …

Dual Orexin Receptor Antagonism With Lemborexant Enhances Microglial Clearance Of Β-Amyloid In Mice, Ashish Sharma, Emiko Segawa, Xiaoying Chen, Sohui Park, Shoutang Wang, Riley E Irmen, Nicholas J Constantino, Chanung Wang, Michael F Kanan, Marco Colonna, Shannon L Macauley, Jocelyn Y Cheng, Ken Hatanaka, Margaret Moline, Erik S Musiek

2020-Current year OA Pubs

BACKGROUND: Sleep disturbances elevate brain amyloid-beta (Aβ) levels and represent a modifiable risk factor for Alzheimer's disease (AD). The orexin/hypocretin system regulates sleep-wake behavior and has emerged as a therapeutic target in AD; however, the effects of FDA-approved dual orexin receptor antagonists (DORAs) on amyloid pathology remain unclear. We compared lemborexant, an FDA-approved DORA, to doxepin, an antihistaminergic sleep medication, on amyloid pathology and microglial responses in PSAPP mice.

METHODS: PSAPP mice received lemborexant (10 or 30 mg/kg/day), doxepin (35 mg/kg/day), or vehicle for 6 weeks beginning prior to plaque onset or 4 weeks after established pathology. Sleep was assessed …

Cd11c+ Cd8 T Cells Cause Ifn-Γ-Dependent Autoimmune Neuroinflammation That Is Restrained By Pd-1 Signaling, Daniel Hwang, Gholamreza Azizi, Larissa Lumi Watanabe Ishikawa, Maryam S. Seyedsadr, Arin Cox, Soohwa Jang, Ezgi Kasimoglu, Abdolmohamad Rostami, Guang-Xian Zhang, Bogoljub Ciric

Department of Neurology Faculty Papers

In multiple sclerosis (MS) lesions, CD8 T cells outnumber CD4 T cells, suggesting that they contribute to MS pathology. However, little is known about the role of CD8 T cells in MS, partly due to the prevalent use of experimental autoimmune encephalomyelitis (EAE) models mediated by CD4 T cells, which have limited involvement of CD8 T cells. Importantly, MS and EAE differ in both their distribution of CNS lesions and neurologic deficits, indicating differences in CNS inflammation. MS lesions are more commonly found in the brain, whereas EAE lesions are more frequent in the spinal cord. Additionally, neurologic deficits in …

Movement-Stabilized Three-Dimensional Optical Recordings Of Membrane Potential Changes And Calcium Dynamics In Hippocampal Ca1 Dendrites, Kevin C Gonzalez, Satoshi Terada, Asako Noguchi, George N Zakka, Cliodhna O'Toole, Giuliana Bilbao, Luke Reynolds, Anna Jász, Borbála Kertész, Zoltán Szadai, Alissa Shen, François St-Pierre, Franck Polleux, Attila Losonczy, Balázs Rózsa

Faculty, Staff and Students Publications

Local dendritic computations are thought to critically influence neuronal signaling and plasticity yet remain largely unexplored in vivo due to challenges in stably imaging small structures at ultrafast timescales. We developed a 3D real-time motion correction platform for movement-stabilized, ultrafast two-photon voltage imaging. By co-labeling CA1 pyramidal neurons with voltage and calcium indicators, we simultaneously measured somato-dendritic and electro-calcium coupling at multiple dendritic sites. We characterized isolated dendritic spikes and distance-dependent backpropagation of naturally occurring and photostimulation-evoked bursts and single spikes. We found that bursts backpropagated more reliably than single spikes, validated that somato-dendritic coupling decreases with distance from soma, …

Target Ii Data Portal: A Multi-Omics Resource For Environmental Toxicant Studies In Mice, Prashant K Kuntala, Benpeng Miao, Deepak Purushotham, Bo Zhang, Daofeng Li, Ting Wang

2020-Current year OA Pubs

The Toxicant Exposures and Responses by Genomic and Epigenomic Regulators of Transcription (TaRGET) program is a multiphase program that aims to understand how environmental factors contribute to disease susceptibility using toxicant-exposed mouse models. Here, we present the TaRGET II Data Portal ( https://data.targetepigenomics.org/ ), a comprehensive repository of multi-omics datasets generated from mice exposed to a range of environmental toxicants, including arsenic (As), lead (Pb), bisphenol A (BPA), tributyltin (TBT), di(2-ethylhexyl) phthalate (DEHP), tetrachlorodibenzo-p-dioxin (TCDD), and ambient air pollution (PM2.5). Epigenomic profiling assays capturing alterations in chromatin accessibility, DNA methylation, gene expression, and histone modifications were produced across multiple research …

Decoding Spatial Transcriptomics Across Multicellular And Subcellular Resolutions, Chongyue Zhao, Hanqiu Zhao, Zhiyu Dai, Et Al.

2020-Current year OA Pubs

Current whole-genome spatial transcriptomics (ST) platforms, which range from multicellular (e.g., Visium) to subcellular resolution (e.g., Visium HD, Stereo-seq), face significant challenges in accurately decomposing or aggregating spots into single cells-the fundamental units of biological activity. To date, most existing computational methods operate at the spot level, and no method has effectively reconstructed transcriptomes at single-cell resolution. In this study, we present STARS (Spatial Transcriptomics across Resolutions for Single Cells). Leveraging Vision Transformer model and contrastive learning, STARS combines high-resolution histology images with spot-level transcriptomics data to reconstruct single-cell-level gene expression from multicellular and subcellular platforms. We demonstrate the advantage …

P300/Cbp Inhibition With Inobrodib In Combination With Gilteritinib And Venetoclax Targets Leukemia Stem Cells In Epigenetic Mutant Aml, Melanie L. Goetz, Jennifer S. Romer-Seibert, Amanda M. Versace, Scott Kogan, Chetan Jeurkar, Robert L. Bowman, Nigel Brooks, Kris Frese, Sara E. Meyer

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Acute myeloid leukemia (AML) is a fatal blood cancer with cytotoxic chemotherapy offering at best 25% 5-year survival. While targeted BCL2 and FLT3 inhibitors venetoclax and gilteritinib are used upfront in the treatment of a subset of adult patients with AML and help to extend the survival of some patients, a curative treatment combination with minimal side effects has yet to be discovered. We find that use of the dual histone acetyltransferase p300/CBP bromodomain inhibitor CCS1477 (inobrodib), together with venetoclax and gilteritinib, virtually eliminates leukemia stem cells in an aggressive preclinical model of DNMT3A/FLT3-mutant AML by impairing pro-oncogenic survival and …

Cardiac Hdac3 Disruption Contributes To Hdac Inhibitor-Induced Qt Prolongation, Jiao Lu, Christopher Ward, Sichong Qian, Lilei Zhang, Jiang Chang, Zheng Sun

Faculty, Staff and Students Publications

Histone deacetylase (HDAC) inhibitors are approved for cancer treatment and are being investigated for a wide range of other diseases. Despite their therapeutic promise, clinical studies have reported cardiac side effects, particularly electrocardiogram (EKG) abnormalities, with QT interval prolongation being one of the most consistently reported findings. The mechanisms underlying these cardiac effects remain unclear. In this study, we investigated the role of HDAC3 in cardiac electrophysiology. We found that postnatal depletion of cardiac HDAC3 in mice caused QT interval prolongation, recapitulating the EKG abnormalities reported with HDAC inhibitor use. Adult-onset inducible depletion of cardiac HDAC3 induced additional EKG abnormalities, …

Abl Kinases Regulate Fgf Signaling Independent Of Crk Phosphorylation To Prevent Peters Anomaly Type Ii, Hao Wu, Yingyu Mao, Qian Wang, Honglian Yu, Michael Bouaziz, Neoklis Makrides, Enpeng Wang, Zhipeng Ding, Anthony J Koleske, Glenn L Radice, Jerry Hsu, Xin Zhang

2020-Current year OA Pubs

Peters anomaly is an anterior segment dysgenesis and a leading cause of congenital corneal opacity. Here, we show that loss of ABL kinases restores lens induction in the absence of FGF signaling but induces Peters anomaly type II independently of ERK signaling, a phenotype also observed with elevated FGF-Ras activity. This defect is rescued by allelic deletion of the ABL substrates CRK and CRKL. Contrary to prevailing models, ABL kinases do not act through direct phosphorylation of CRK proteins; instead, they phosphorylate PTPN12, suppressing p130CAS phosphorylation and CRK recruitment required for RHO GTPase activation. ABL kinase deficiency reduces actomyosin contractility …

Wnt-Dependent Ontogeny Of Acellular Cementum-Forming Cementoblasts On The Tooth Root Surface, Taishi Komori, Mizuki Nagata, Natnicha Praneetpong, Hanwen Fan, Yuxiao Zhou, Noriaki Ono, Wanida Ono

Faculty, Staff and Student Publications

Cementum is a specialized mineralized tissue that covers the tooth root surface and anchors the tooth to the surrounding periodontal ligament. The cervical acellular cementum (AC) is indispensable for periodontal attachment and represents a key target for periodontal regenerative therapies. However, the developmental origin and molecular identity of AC-forming cementoblasts remain poorly understood. Here, through an integrated spatial and single-cell transcriptomic analysis, we identify AC-forming cementoblasts as a distinct population of noncanonical mineralizing cells enriched for cell-matrix organization and Wnt signaling signatures, distinguishing them from cellular cementum-forming cementoblasts localized in the apical portion. Lineage tracing using a Wnt inhibitory factor …

Selective And Differential Roles Of Pvhcrh Neurotransmitters In Diet-Induced Obesity In Mice, Zhiying Jiang, Yuhan Cao, Michelle He, Cunjin Su, Runzhou Yang, Maojie Yang, Jing Cai, Hongli Li, Yuanzhong Xu, Shi-Bin Li, Hiroshi Yamaguchi, Luis De Lecea, Benjamin R Arenkiel, Qingchun Tong

The Brown Foundation: Institute of Molecular Medicine

Stress and diet are known to synergistically promote risks of obesity but the underlying neural basis remains elusive. Corticotropin-releasing hormone neurons in the paraventricular hypothalamus (PVHCRH) are stress responsive and release both CRH and glutamate. Here we generated a mouse model with gain or loss of release in CRH or glutamate from PVHCRH neurons. While these models showed no changes in body weight when fed chow, they exhibited contrasting effects when fed high-fat high-caloric diets (HFD). Whereas disrupting glutamate release from PVHCRH neurons led to diet-induced obesity (DIO), that of CRH caused no impact. Conversely, augmented CRH release led to …

Type-1 Ryanodine Receptor Plays An Important Role In Cardiac Hypertrophy And Heart Failure By Increasing Type-2 Ryanodine Receptor-Mediated Calcium Release, Yong-Xiao Wang, Ed Wilson Santos, Sarahann Mistretta, Yuexing Yuan, Harold A. Singer, Shey-Shing Sheu, Yun-Min Zheng

Center for Translational Medicine Faculty Papers

Type-1 ryanodine receptor (RyR1) is essential for skeletal muscle contraction. This Ca²⁺ release channel is expressed in cardiac myocytes; however, its function remains elusive. Cardiac-specific RyR1 overexpression (OE) mice were generated under the cardiac-specific Myh6 promoter. Cardiac hypertrophy (CH), cardiac functions, and mechanistic changes in RyR1 OE and control (wildtype, WT) mice were assessed using hematoxylin and eosin staining, echocardiography, electrocardiogram, quantitative RT-PCR, Western blotting, [³H]-ryanodine binding assay, confocal microscope, ROS dye Amplex Red and 2′,7′-dichlorofluorescein diacetate. RyR1 OE mice had increased whole heart, left ventricular weight, and left ventricular wall thickness, but decreased cardiac output and …

Volume Electron Microscopy Reveals Heterogeneity Of The Hemostatic Response In Veins And Arteries, Maurizio Tomaiuolo, Meghan E. Roberts, Jenna R. Severa, Christopher D. Mansi, Brenna B. Y. Mathers, Anna Mannix, Trace A Christensen, Lawrence F Brass, Talid Sinno, Timothy J. Stalker

Cardeza Foundation for Hematologic Research

Intravital imaging studies have provided insights into the spatial and temporal variations of platelet activation and thrombin generation that occur during hemostasis; however, these studies are generally limited to small vessels due to the practical limitations of imaging in thicker tissues. Recent advances in cleared tissue fluorescence imaging as well as volume electron microscopy (vEM) coupled with machine learning-based image segmentation provide an opportunity for analysis of the 3-dimensional structure of complex tissues. We utilized these technologies to examine hemostatic plugs from murine jugular veins and carotid arteries to investigate the spatial distribution of platelet activation and biochemical responses in …

Water-Soluble Fullerene Derivatives Mitigate Cranial Radiation-Induced Neuroinflammation And Cognitive Dysfunction, Naren Gundapaneni, Iona Hill, Lydia W T Cheung, Khadijeh Koushki, Alyssa Fausnaught, Phuoc Minh Quan Mai, Arjun Vasan, Prapannajeet Biswal, Ashutosh Tripathi, Anilkumar Pillai, Vijayasree V Giridharan, Tatiana Barichello, Yuri Mackeyev, Sunil Krishnan

Faculty, Staff and Student Publications

Radiotherapy is widely used to treat malignant and benign brain tumors. A major constraint, however, is the low tolerance of normal brain tissue to radiation. Cranial irradiation-induced injury manifests as inflammatory responses and neurodegeneration, which jointly contribute to progressive cognitive decline. These complications can restrict the delivery of optimal therapeutic doses, cause persistent neurological symptoms, and ultimately compromise quality of life. Thus, neuroprotective agents have emerged as a strategy to safeguard normal tissues from radiation-induced neurotoxicity. This study investigated the efficacy of a highly soluble [60]fullerene (C60) derivative, C60-ser, a carbon-based nanomaterial, to mitigate radiation-induced brain injury. Oral administration of …

Tunable Tripcides Suppress Virulence Factor Secretion During Staphylococcus Aureus Infection And Kill Dormant Cells, Hasan Tükenmez, Taylor M Nye, Suzanne Hickerson, Chloe L P Obernuefemann, Jerome S Pinkner, Karen W Dodson, Michael G Caparon, Scott J Hultgren, Et Al.

2020-Current year OA Pubs

Antimicrobial resistance (AMR) in common bacterial pathogens, including methicillin-resistant

Progressive Cardiac Phenotypes And Reduced Reversibility From Long-Term Cugexp Rna Expression In A Dm1 Mouse Model, Rong-Chi Hu, Mohammadreza Tabary, Xander Ht Wehrens, Thomas A Cooper

Faculty, Staff and Students Publications

Myotonic dystrophy type 1 (DM1) is caused by an expanded CTG repeat in the DMPK gene, resulting in mutant transcripts that form expanded CUG (CUGexp) RNA foci and sequester muscleblind-like (MBNL) RNA-binding proteins. DM1 is multisystemic, with progressive worsening of disease manifestations in affected tissues. Disease progression is attributed to somatic expansion of the CTG repeats with age, resulting in production of CUGexp RNA with enhanced intrinsic toxicity due to increased MBNL sequestration. To determine the degree to which cardiac disease progression can occur independently of repeat expansion, we used a transgenic DM1 mouse model with inducible heart-specific expression of …

Gut Microbiota Modulation Of Regulatory Dna Elements Revealed By Massively Parallel Functional Characterization, Chadmirah Zaratiana, Adheet Ganesh, Yang E Li, Et Al.

2020-Current year OA Pubs

Cis-regulatory elements (CREs) are central to dynamic gene regulation in hepatocytes, yet most functional annotations derive from in vitro models that poorly capture physiological regulation. We systematically profiled 109,386 human liver-derived CREs using massively parallel reporter assays in hepatocytes under matched in vitro and in vivo conditions. In vivo-active functional CREs (fCREs) were enriched for H3K27ac and chromatin accessibility and were regulated by diverse transcription factors in the human liver. We further demonstrate that gut microbiota-derived signals modulate fCRE activity and target gene expression in vivo, in part via the KEAP1/NFE2L2 antioxidant pathway. Specific microbial metabolites directly altered the activity …

+Cd49a+Cd103+ Cytotoxic Tissue-Resident Natural Killer Cells Infiltrate And Control Solid Epithelial Tumor Growth In Mice, Nina B Horowitz, Jennifer A Foltz, Et Al.

2020-Current year OA Pubs

Human tissue-resident natural killer (NK) cells (trNK cells), broadly defined by markers of tissue residency, such as CD49a [