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Metagenomic Analysis Of Dna Viruses With Targeted Sequence Capture Of Canine Lobular Orbital Adenomas And Normal Conjunctiva, Elizabeth A F Schaefer, Shirley Chu, Kristine M Wylie, Todd N Wylie, Obi L Griffith, Jacqueline W Pearce, Gayle C Johnson, Jeffrey N Bryan, Brian K Flesner Apr 2023

Metagenomic Analysis Of Dna Viruses With Targeted Sequence Capture Of Canine Lobular Orbital Adenomas And Normal Conjunctiva, Elizabeth A F Schaefer, Shirley Chu, Kristine M Wylie, Todd N Wylie, Obi L Griffith, Jacqueline W Pearce, Gayle C Johnson, Jeffrey N Bryan, Brian K Flesner

2020-Current year OA Pubs

Our study aims are: (1) to evaluate phenotypically normal canine conjunctival and orbital tissue and tissue from canine lobular orbital adenomas (CLOAs) for the presence of viral genomic material and (2) phylogenetically classify detected DNA viruses to determine if a DNA virus is associated with CLOAs. A total of 31 formalin fixed paraffin embedded CLOA tissue samples, 4 papillomas or sarcoid, and 10 fresh clinically normal conjunctival tissues were included in this study. Genomic DNA was isolated from all samples and sequencing libraries were prepared. The libraries were molecularly indexed and pooled and viral DNA was enriched via targeted sequence …


Abrogation Of Map4k4 Protein Function Causes Congenital Anomalies In Humans And Zebrafish, Victoria Patterson, Dorothy K Grange, Et Al. Apr 2023

Abrogation Of Map4k4 Protein Function Causes Congenital Anomalies In Humans And Zebrafish, Victoria Patterson, Dorothy K Grange, Et Al.

2020-Current year OA Pubs

We report 21 families displaying neurodevelopmental differences and multiple congenital anomalies while bearing a series of rare variants in


Inulin Diet Uncovers Complex Diet-Microbiota-Immune Cell Interactions Remodeling The Gut Epithelium, Renan Oliveira Corrêa, José Luís Fachi, Marco Colonna, Et Al. Apr 2023

Inulin Diet Uncovers Complex Diet-Microbiota-Immune Cell Interactions Remodeling The Gut Epithelium, Renan Oliveira Corrêa, José Luís Fachi, Marco Colonna, Et Al.

2020-Current year OA Pubs

BACKGROUND: The continuous proliferation of intestinal stem cells followed by their tightly regulated differentiation to epithelial cells is essential for the maintenance of the gut epithelial barrier and its functions. How these processes are tuned by diet and gut microbiome is an important, but poorly understood question. Dietary soluble fibers, such as inulin, are known for their ability to impact the gut bacterial community and gut epithelium, and their consumption has been usually associated with health improvement in mice and humans. In this study, we tested the hypothesis that inulin consumption modifies the composition of colonic bacteria and this impacts …


Site-1 Protease Inhibits Mitochondrial Respiration By Controlling The Tgf-Β Target Gene Mss51, Muhammad G Mousa, Lahari Vuppaladhadiam, Meredith O Kelly, Terri Pietka, Shelby Ek, Karen C Shen, Gretchen A Meyer, Brian N Finck, Rita T Brookheart Apr 2023

Site-1 Protease Inhibits Mitochondrial Respiration By Controlling The Tgf-Β Target Gene Mss51, Muhammad G Mousa, Lahari Vuppaladhadiam, Meredith O Kelly, Terri Pietka, Shelby Ek, Karen C Shen, Gretchen A Meyer, Brian N Finck, Rita T Brookheart

2020-Current year OA Pubs

The mitochondrial response to changes in cellular energy demand is necessary for cellular adaptation and organ function. Many genes are essential in orchestrating this response, including the transforming growth factor (TGF)-β1 target gene Mss51, an inhibitor of skeletal muscle mitochondrial respiration. Although Mss51 is implicated in the pathophysiology of obesity and musculoskeletal disease, how Mss51 is regulated is not entirely understood. Site-1 protease (S1P) is a key activator of several transcription factors required for cellular adaptation. However, the role of S1P in muscle is unknown. Here, we identify S1P as a negative regulator of muscle mass and mitochondrial respiration. S1P …


Transcriptomic Atlas And Interaction Networks Of Brain Cells In Mouse Cns Demyelination And Remyelination, Jinchao Hou, Yingyue Zhou, Zhangying Cai, Marina Terekhova, Amanda Swain, Prabhakar S Andhey, Rafaela M Guimaraes, Alina Ulezko Antonova, Tian Qiu, Sanja Sviben, Gregory Strout, James A J Fitzpatrick, Yun Chen, Susan Gilfillan, Do-Hyun Kim, Steven J Van Dyken, Maxim N Artyomov, Marco Colonna Apr 2023

Transcriptomic Atlas And Interaction Networks Of Brain Cells In Mouse Cns Demyelination And Remyelination, Jinchao Hou, Yingyue Zhou, Zhangying Cai, Marina Terekhova, Amanda Swain, Prabhakar S Andhey, Rafaela M Guimaraes, Alina Ulezko Antonova, Tian Qiu, Sanja Sviben, Gregory Strout, James A J Fitzpatrick, Yun Chen, Susan Gilfillan, Do-Hyun Kim, Steven J Van Dyken, Maxim N Artyomov, Marco Colonna

2020-Current year OA Pubs

Demyelination is a hallmark of multiple sclerosis, leukoencephalopathies, cerebral vasculopathies, and several neurodegenerative diseases. The cuprizone mouse model is widely used to simulate demyelination and remyelination occurring in these diseases. Here, we present a high-resolution single-nucleus RNA sequencing (snRNA-seq) analysis of gene expression changes across all brain cells in this model. We define demyelination-associated oligodendrocytes (DOLs) and remyelination-associated MAFB


Advances In Mass Spectrometry On Membrane Proteins, Hsin-Chieh Yang, Weikai Li, Jie Sun, Michael L Gross Apr 2023

Advances In Mass Spectrometry On Membrane Proteins, Hsin-Chieh Yang, Weikai Li, Jie Sun, Michael L Gross

2020-Current year OA Pubs

Understanding the higher-order structure of membrane proteins (MPs), which are vital for numerous biological processes, is crucial for comprehending their function. Although several biophysical approaches have been used to study the structure of MPs, limitations exist owing to the proteins' dynamic nature and heterogeneity. Mass spectrometry (MS) is emerging as a powerful tool for investigating membrane protein structure and dynamics. Studying MPs using MS, however, must meet several challenges including the lack of stability and solubility of MPs, the complexity of the protein-membrane system, and the difficulty of digestion and detection. To meet these challenges, recent advances in MS have …


Mutational Analysis Of Anesthetic Binding Sites And Their Effects On Gabaa Receptor Activation And Modulation By Positive Allosteric Modulators Of The Α7 Nicotinic Receptor, Spencer R Pierce, Allison L Germann, Sophia Q Xu, Saumith L Menon, Marcelo O Ortells, Hugo R Arias, Gustav Akk Apr 2023

Mutational Analysis Of Anesthetic Binding Sites And Their Effects On Gabaa Receptor Activation And Modulation By Positive Allosteric Modulators Of The Α7 Nicotinic Receptor, Spencer R Pierce, Allison L Germann, Sophia Q Xu, Saumith L Menon, Marcelo O Ortells, Hugo R Arias, Gustav Akk

2020-Current year OA Pubs

The positive allosteric modulators (PAMs) of the α7 nicotinic receptor


Reversing Dysdynamism To Interrupt Mitochondrial Degeneration In Amyotrophic Lateral Sclerosis, Gerald W Dorn Ii Apr 2023

Reversing Dysdynamism To Interrupt Mitochondrial Degeneration In Amyotrophic Lateral Sclerosis, Gerald W Dorn Ii

2020-Current year OA Pubs

Amyotrophic lateral sclerosis is one of several chronic neurodegenerative conditions in which mitochondrial abnormalities are posited to contribute to disease progression. Therapeutic options targeting mitochondria include enhancing metabolism, suppressing reactive oxygen production and disrupting mitochondria-mediated programmed cell death pathways. Herein is reviewed mechanistic evidence supporting a meaningful pathophysiological role for the constellation of abnormal mitochondrial fusion, fission and transport, collectively designated mitochondrial dysdynamism, in ALS. Following this is a discussion on preclinical studies in ALS mice that seemingly validate the idea that normalizing mitochondrial dynamism can delay ALS by interrupting a vicious cycle of mitochondrial degeneration, leading to neuronal die-back …


A Somato-Cognitive Action Network Alternates With Effector Regions In Motor Cortex, Evan M Gordon, Roselyne J Chauvin, Andrew N Van, Aishwarya Rajesh, Ashley Nielsen, Dillan J Newbold, Nicole A Seider, Samuel R Krimmel, Kristen M Scheidter, Julia Monk, Ryland L Miller, Athanasia Metoki, David F Montez, Annie Zheng, Tomoyuki Nishino, Michael J Myers, Sydney Kaplan, Carolina Badke D'Andrea, Deanna M Barch, Christopher D Smyser, Cynthia E Rogers, Kelly N Botteron, John R Pruett, Jon T Willie, Peter Brunner, Joshua S Shimony, Benjamin P Kay, Scott Marek, Scott A Norris, Chad M Sylvester, Jarod L Roland, Steven E Petersen, Marcus E Raichle, Timothy O Laumann, Nico U F Dosenbach, Et Al. Apr 2023

A Somato-Cognitive Action Network Alternates With Effector Regions In Motor Cortex, Evan M Gordon, Roselyne J Chauvin, Andrew N Van, Aishwarya Rajesh, Ashley Nielsen, Dillan J Newbold, Nicole A Seider, Samuel R Krimmel, Kristen M Scheidter, Julia Monk, Ryland L Miller, Athanasia Metoki, David F Montez, Annie Zheng, Tomoyuki Nishino, Michael J Myers, Sydney Kaplan, Carolina Badke D'Andrea, Deanna M Barch, Christopher D Smyser, Cynthia E Rogers, Kelly N Botteron, John R Pruett, Jon T Willie, Peter Brunner, Joshua S Shimony, Benjamin P Kay, Scott Marek, Scott A Norris, Chad M Sylvester, Jarod L Roland, Steven E Petersen, Marcus E Raichle, Timothy O Laumann, Nico U F Dosenbach, Et Al.

2020-Current year OA Pubs

Motor cortex (M1) has been thought to form a continuous somatotopic homunculus extending down the precentral gyrus from foot to face representations


Dendritic Cells And Cryptosporidium: From Recognition To Restriction, Iti Saraav, L David Sibley Apr 2023

Dendritic Cells And Cryptosporidium: From Recognition To Restriction, Iti Saraav, L David Sibley

2020-Current year OA Pubs

Host immune responses are required for the efficient control of cryptosporidiosis. Immunity against


Structure Of Anhydrotetracycline-Bound Tet(X6) Reveals The Mechanism For Inhibition Of Type 1 Tetracycline Destructases, Hirdesh Kumar, Emily E Williford, Kevin S Blake, Brett Virgin-Downey, Gautam Dantas, Timothy A Wencewicz, Niraj H Tolia Apr 2023

Structure Of Anhydrotetracycline-Bound Tet(X6) Reveals The Mechanism For Inhibition Of Type 1 Tetracycline Destructases, Hirdesh Kumar, Emily E Williford, Kevin S Blake, Brett Virgin-Downey, Gautam Dantas, Timothy A Wencewicz, Niraj H Tolia

2020-Current year OA Pubs

Inactivation of tetracycline antibiotics by tetracycline destructases (TDases) remains a clinical and agricultural threat. TDases can be classified as type 1 Tet(X)-like TDases and type 2 soil-derived TDases. Type 1 TDases are widely identified in clinical pathogens. A combination therapy of tetracycline and a TDase inhibitor is much needed to rescue the clinical efficacy of tetracyclines. Anhydrotetracycline is a pan-TDase inhibitor that inhibits both type 1 and type 2 TDases. Here, we present structural, biochemical, and phenotypic evidence that anhydrotetracycline binds in a substrate-like orientation and competitively inhibits the type 1 TDase Tet(X6) to rescue tetracycline antibiotic activity as a …


Spike-Phase Coupling Patterns Reveal Laminar Identity In Primate Cortex, Zachary W Davis, Nicholas M Dotson, Tom P Franken, Lyle Muller, John H Reynolds Apr 2023

Spike-Phase Coupling Patterns Reveal Laminar Identity In Primate Cortex, Zachary W Davis, Nicholas M Dotson, Tom P Franken, Lyle Muller, John H Reynolds

2020-Current year OA Pubs

The cortical column is one of the fundamental computational circuits in the brain. In order to understand the role neurons in different layers of this circuit play in cortical function it is necessary to identify the boundaries that separate the laminar compartments. While histological approaches can reveal ground truth they are not a practical means of identifying cortical layers in vivo. The gold standard for identifying laminar compartments in electrophysiological recordings is current-source density (CSD) analysis. However, laminar CSD analysis requires averaging across reliably evoked responses that target the input layer in cortex, which may be difficult to generate in …


Simultaneous Inhibition Of Thrombosis And Inflammation Is Beneficial In Treating Acute Myocardial Infarction, Ian Vargas, Ryan P Grabau, Junjie Chen, Carla Weinheimer, Attila Kovacs, William Dominguez-Viqueira, Adam Mitchell, Samuel A Wickline, Hua Pan Apr 2023

Simultaneous Inhibition Of Thrombosis And Inflammation Is Beneficial In Treating Acute Myocardial Infarction, Ian Vargas, Ryan P Grabau, Junjie Chen, Carla Weinheimer, Attila Kovacs, William Dominguez-Viqueira, Adam Mitchell, Samuel A Wickline, Hua Pan

2020-Current year OA Pubs

Myocardial ischemia reperfusion injury (IRI) in acute coronary syndromes is a condition in which ischemic/hypoxic injury to cells subtended by the occluded vessel continues despite successful resolution of the thrombotic obstruction. For decades, most efforts to attenuate IRI have focused on interdicting singular molecular targets or pathways, but none have successfully transitioned to clinical use. In this work, we investigate a nanoparticle-based therapeutic strategy for profound but local thrombin inhibition that may simultaneously mitigate both thrombosis and inflammatory signaling pathways to limit myocardial IRI. Perfluorocarbon nanoparticles (PFC NP) were covalently coupled with an irreversible thrombin inhibitor, PPACK (Phe[D]-Pro-Arg-Chloromethylketone), and delivered …


Mek Inhibition Synergizes With Tyk2 Inhibitors In Nf1-Associated Malignant Peripheral Nerve Sheath Tumors, Dana C Borcherding, Neha V Amin, Kevin He, Xiaochun Zhang, Yang Lyu, Carina Dehner, Himanshi Bhatia, Angad Gothra, Layla Daud, Peter Ruminski, Christine A Pratilas, Kai Pollard, Taylor Sundby, Brigitte C Widemann, Angela C Hirbe Apr 2023

Mek Inhibition Synergizes With Tyk2 Inhibitors In Nf1-Associated Malignant Peripheral Nerve Sheath Tumors, Dana C Borcherding, Neha V Amin, Kevin He, Xiaochun Zhang, Yang Lyu, Carina Dehner, Himanshi Bhatia, Angad Gothra, Layla Daud, Peter Ruminski, Christine A Pratilas, Kai Pollard, Taylor Sundby, Brigitte C Widemann, Angela C Hirbe

2020-Current year OA Pubs

PURPOSE: Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas with limited treatment options and poor survival rates. About half of MPNST cases are associated with the neurofibromatosis type 1 (NF1) cancer predisposition syndrome. Overexpression of TYK2 occurs in the majority of MPNST, implicating TYK2 as a therapeutic target.

EXPERIMENTAL DESIGN: The effects of pharmacologic TYK2 inhibition on MPNST cell proliferation and survival were examined using IncuCyte live cell assays in vitro, and downstream actions were analyzed using RNA-sequencing (RNA-seq), qPCR arrays, and validation of protein changes with the WES automated Western system. Inhibition of TYK2 alone and in combination …


Integrated Model Of The Vertebrate Augmin Complex, Sophie M Travis, Brian P Mahon, Wei Huang, Meisheng Ma, Michael J Rale, Jodi Kraus, Derek J Taylor, Rui Zhang, Sabine Petry Apr 2023

Integrated Model Of The Vertebrate Augmin Complex, Sophie M Travis, Brian P Mahon, Wei Huang, Meisheng Ma, Michael J Rale, Jodi Kraus, Derek J Taylor, Rui Zhang, Sabine Petry

2020-Current year OA Pubs

Accurate segregation of chromosomes is required to maintain genome integrity during cell division. This feat is accomplished by the microtubule-based spindle. To build a spindle rapidly and with high fidelity, cells take advantage of branching microtubule nucleation, which rapidly amplifies microtubules during cell division. Branching microtubule nucleation relies on the hetero-octameric augmin complex, but lack of structure information about augmin has hindered understanding how it promotes branching. In this work, we combine cryo-electron microscopy, protein structural prediction, and visualization of fused bulky tags via negative stain electron microscopy to identify the location and orientation of each subunit within the augmin …


Isoflurane Conditioning Provides Protection Against Subarachnoid Hemorrhage Induced Delayed Cerebral Ischemia Through Nf-Kb Inhibition, Meizi Liu, Keshav Jayaraman, Jogender Mehla, Deepti Diwan, James W Nelson, Ahmed E Hussein, Ananth K Vellimana, Yousef Abu-Amer, Gregory J Zipfel, Umeshkumar Athiraman Apr 2023

Isoflurane Conditioning Provides Protection Against Subarachnoid Hemorrhage Induced Delayed Cerebral Ischemia Through Nf-Kb Inhibition, Meizi Liu, Keshav Jayaraman, Jogender Mehla, Deepti Diwan, James W Nelson, Ahmed E Hussein, Ananth K Vellimana, Yousef Abu-Amer, Gregory J Zipfel, Umeshkumar Athiraman

2020-Current year OA Pubs

Delayed cerebral ischemia (DCI) is the largest treatable cause of poor outcome after aneurysmal subarachnoid hemorrhage (SAH). Nuclear Factor Kappa-light-chain-enhancer of Activated B cells (NF-kB), a transcription factor known to function as a pivotal mediator of inflammation, is upregulated in SAH and is pathologically associated with vasospasm. We previously showed that a brief exposure to isoflurane, an inhalational anesthetic, provided multifaceted protection against DCI after SAH. The aim of our current study is to investigate the role of NF-kB in isoflurane-conditioning-induced neurovascular protection against SAH-induced DCI. Twelve-week-old wild type male mice (C57BL/6) were divided into five groups: sham, SAH, SAH …


Sleep-Wake Patterns Are Altered With Age, Prdm13 Signaling In The Dmh, And Diet Restriction In Mice, Shogo Tsuji, Cynthia S Brace, Nicholas Rensing, Michael Wong, Shin-Ichiro Imai, Et Al. Apr 2023

Sleep-Wake Patterns Are Altered With Age, Prdm13 Signaling In The Dmh, And Diet Restriction In Mice, Shogo Tsuji, Cynthia S Brace, Nicholas Rensing, Michael Wong, Shin-Ichiro Imai, Et Al.

2020-Current year OA Pubs

Old animals display significant alterations in sleep-wake patterns such as increases in sleep fragmentation and sleep propensity. Here, we demonstrated that PR-domain containing protein 13 (Prdm13)+ neurons in the dorsomedial hypothalamus (DMH) are activated during sleep deprivation (SD) in young mice but not in old mice. Chemogenetic inhibition of Prdm13+ neurons in the DMH in young mice promotes increase in sleep attempts during SD, suggesting its involvement in sleep control. Furthermore, DMH-specific


Sting-Dependent Interferon Signatures Restrict Osteoclast Differentiation And Bone Loss In Mice, Susan Maclauchlan, Priyanka Kushwaha, Albert Tai, Sijia Chen, Catherine Manning, Gaurav Swarnkar, Yousef Abu-Amer, Katherine A Fitzgerald, Shruti Sharma, Ellen M Gravallese Apr 2023

Sting-Dependent Interferon Signatures Restrict Osteoclast Differentiation And Bone Loss In Mice, Susan Maclauchlan, Priyanka Kushwaha, Albert Tai, Sijia Chen, Catherine Manning, Gaurav Swarnkar, Yousef Abu-Amer, Katherine A Fitzgerald, Shruti Sharma, Ellen M Gravallese

2020-Current year OA Pubs

Stimulator of interferon genes (STING) is a key mediator of type-I interferon (IFN-I) signaling in response to a variety of stimuli, but the contribution of STING to homeostatic processes is not fully characterized. Previous studies showed that ligand activation of STING limits osteoclast differentiation in vitro through the induction of IFNβ and IFN-I interferon-stimulated genes (ISGs). In a disease model (SAVI) driven by the V154M gain-of-function mutation in STING, fewer osteoclasts form from SAVI precursors in response to receptor activator of NF-kappaB ligand (RANKL) in an IFN-I-dependent manner. Due to the described role of STING-mediated regulation of osteoclastogenesis in activation …


Il-15 Enhances Hiv-1 Infection By Promoting Survival And Proliferation Of Ccr5+Cd4+ T Cells, Yuhao Li, Hongbo Gao, Kolin M. Clark, Liang Shan Apr 2023

Il-15 Enhances Hiv-1 Infection By Promoting Survival And Proliferation Of Ccr5+Cd4+ T Cells, Yuhao Li, Hongbo Gao, Kolin M. Clark, Liang Shan

2020-Current year OA Pubs

HIV-1 usually utilizes CCR5 as its coreceptor and rarely switches to a CXCR4-tropic virus until the late stage of infection. CCR5+CD4+ T cells are the major virus-producing cells in viremic individuals as well as SIV-infected nonhuman primates. The differentiation of CCR5+CD4+ T cells is associated with the availability of IL-15, which increases during acute HIV-1 infection. Here, we report that CCR5 was expressed by CD4+ T cells exhibiting effector or effector memory phenotypes with high expression levels of the IL-2/IL-15 receptor common β and γ chains. IL-15, but not IL-7, improved the survival of CCR5+CD4+ T cells, drove their expansion, …


Neuronal Birthdate Reveals Topography In A Vestibular Brainstem Circuit For Gaze Stabilization, Dena Goldblatt, Stephanie Huang, Marie R Greaney, Kyla R Hamling, Venkatakaushik Voleti, Citlali Perez-Campos, Kripa B Patel, Wenze Li, Elizabeth M C Hillman, Martha W Bagnall, David Schoppik Apr 2023

Neuronal Birthdate Reveals Topography In A Vestibular Brainstem Circuit For Gaze Stabilization, Dena Goldblatt, Stephanie Huang, Marie R Greaney, Kyla R Hamling, Venkatakaushik Voleti, Citlali Perez-Campos, Kripa B Patel, Wenze Li, Elizabeth M C Hillman, Martha W Bagnall, David Schoppik

2020-Current year OA Pubs

Across the nervous system, neurons with similar attributes are topographically organized. This topography reflects developmental pressures. Oddly, vestibular (balance) nuclei are thought to be disorganized. By measuring activity in birthdated neurons, we revealed a functional map within the central vestibular projection nucleus that stabilizes gaze in the larval zebrafish. We first discovered that both somatic position and stimulus selectivity follow projection neuron birthdate. Next, with electron microscopy and loss-of-function assays, we found that patterns of peripheral innervation to projection neurons were similarly organized by birthdate. Finally, birthdate revealed spatial patterns of axonal arborization and synapse formation to projection neuron outputs. …


Uropathogenic Escherichia Coli Infection-Induced Epithelial Trained Immunity Impacts Urinary Tract Disease Outcome, Seongmi K Russell, Jessica K Harrison, Benjamin S Olson, Hyung Joo Lee, Valerie P O'Brien, Xiaoyun Xing, Lu Yu, Elisha D O Roberson, Rajdeep Bomjan, Changxu Fan, Marina Sha, Marco Colonna, Ting Wang, Thomas J Hannan, Scott J Hultgren, Et Al. Apr 2023

Uropathogenic Escherichia Coli Infection-Induced Epithelial Trained Immunity Impacts Urinary Tract Disease Outcome, Seongmi K Russell, Jessica K Harrison, Benjamin S Olson, Hyung Joo Lee, Valerie P O'Brien, Xiaoyun Xing, Lu Yu, Elisha D O Roberson, Rajdeep Bomjan, Changxu Fan, Marina Sha, Marco Colonna, Ting Wang, Thomas J Hannan, Scott J Hultgren, Et Al.

2020-Current year OA Pubs

Previous urinary tract infections (UTIs) can predispose one to future infections; however, the underlying mechanisms affecting recurrence are poorly understood. We previously found that UTIs in mice cause differential bladder epithelial (urothelial) remodelling, depending on disease outcome, that impacts susceptibility to recurrent UTI. Here we compared urothelial stem cell (USC) lines isolated from mice with a history of either resolved or chronic uropathogenic Escherichia coli (UPEC) infection, elucidating evidence of molecular imprinting that involved epigenetic changes, including differences in chromatin accessibility, DNA methylation and histone modification. Epigenetic marks in USCs from chronically infected mice enhanced caspase-1-mediated cell death upon UPEC …


Sphingomyelin 16:0 Is A Therapeutic Target For Neuronal Death In Acid Sphingomyelinase Deficiency, Ángel Gaudioso, Xuntian Jiang, Josefina Casas, Edward H Schuchman, María Dolores Ledesma Apr 2023

Sphingomyelin 16:0 Is A Therapeutic Target For Neuronal Death In Acid Sphingomyelinase Deficiency, Ángel Gaudioso, Xuntian Jiang, Josefina Casas, Edward H Schuchman, María Dolores Ledesma

2020-Current year OA Pubs

Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disorder caused by mutations in the SMPD1 gene encoding for the acid sphingomyelinase (ASM). While intravenous infusion of recombinant ASM is an effective treatment for the peripheral disease, the neurological complications of ASMD remain unaddressed. It has been shown that aberrantly high level of total brain sphingomyelin (SM) is a key pathological event leading to neurodegeneration. Using mice lacking ASM (ASMko), which mimic the disease, we here demonstrate that among the SM species, SM16:0 shows the highest accumulation and toxicity in ASMko neurons. By targeting lysosomes, SM16:0 causes permeabilization and exocytosis of …


The F-Pilus Biomechanical Adaptability Accelerates Conjugative Dissemination Of Antimicrobial Resistance And Biofilm Formation, Jonasz B Patkowski, Tobias Dahlberg, Himani Amin, Dharmender K Gahlot, Sukhithasri Vijayrajratnam, Joseph P Vogel, Matthew S Francis, Joseph L Baker, Magnus Andersson, Tiago R D Costa Apr 2023

The F-Pilus Biomechanical Adaptability Accelerates Conjugative Dissemination Of Antimicrobial Resistance And Biofilm Formation, Jonasz B Patkowski, Tobias Dahlberg, Himani Amin, Dharmender K Gahlot, Sukhithasri Vijayrajratnam, Joseph P Vogel, Matthew S Francis, Joseph L Baker, Magnus Andersson, Tiago R D Costa

2020-Current year OA Pubs

Conjugation is used by bacteria to propagate antimicrobial resistance (AMR) in the environment. Central to this process are widespread conjugative F-pili that establish the connection between donor and recipient cells, thereby facilitating the spread of IncF plasmids among enteropathogenic bacteria. Here, we show that the F-pilus is highly flexible but robust at the same time, properties that increase its resistance to thermochemical and mechanical stresses. By a combination of biophysical and molecular dynamics methods, we establish that the presence of phosphatidylglycerol molecules in the F-pilus contributes to the structural stability of the polymer. Moreover, this structural stability is important for …


Statins Enhance The Efficacy Of Her2-Targeting Radioligand Therapy In Drug-Resistant Gastric Cancers, Yi Rao, Zachary Samuels, Lukas M Carter, Sebastien Monette, Sandeep Surendra Panikar, Patricia M R Pereira, Jason S Lewis Apr 2023

Statins Enhance The Efficacy Of Her2-Targeting Radioligand Therapy In Drug-Resistant Gastric Cancers, Yi Rao, Zachary Samuels, Lukas M Carter, Sebastien Monette, Sandeep Surendra Panikar, Patricia M R Pereira, Jason S Lewis

2020-Current year OA Pubs

Human epidermal growth factor receptor 2 (HER2) is overexpressed in various cancer types. HER2-targeting trastuzumab plus chemotherapy is used as first-line therapy for HER2-positive recurrent or primary metastatic gastric cancer, but intrinsic and acquired trastuzumab resistance inevitably develop over time. To overcome gastric cancer resistance to HER2-targeted therapies, we have conjugated trastuzumab with a beta-emitting therapeutic isotope, lutetium-177, to deliver radiation locally to gastric tumors with minimal toxicity. Because trastuzumab-based targeted radioligand therapy (RLT) requires only the extramembrane domain binding of membrane-bound HER2 receptors, HER2-targeting RLT can bypass any resistance mechanisms that occur downstream of HER2 binding. Leveraging our previous …


Monocyte Depletion Enhances Neutrophil Influx And Proneural To Mesenchymal Transition In Glioblastoma, Zhihong Chen, David H Gutmann, Et Al. Apr 2023

Monocyte Depletion Enhances Neutrophil Influx And Proneural To Mesenchymal Transition In Glioblastoma, Zhihong Chen, David H Gutmann, Et Al.

2020-Current year OA Pubs

Myeloid cells comprise the majority of immune cells in tumors, contributing to tumor growth and therapeutic resistance. Incomplete understanding of myeloid cells response to tumor driver mutation and therapeutic intervention impedes effective therapeutic design. Here, by leveraging CRISPR/Cas9-based genome editing, we generate a mouse model that is deficient of all monocyte chemoattractant proteins. Using this strain, we effectively abolish monocyte infiltration in genetically engineered murine models of de novo glioblastoma (GBM) and hepatocellular carcinoma (HCC), which show differential enrichment patterns for monocytes and neutrophils. Eliminating monocyte chemoattraction in monocyte enriched PDGFB-driven GBM invokes a compensatory neutrophil influx, while having no …


Baseline Characteristics Of The North American Prodromal Synucleinopathy Cohort, Jonathan E Elliott, Jennifer Mcleland, Susan R Criswell, Yo-El S Ju, Et Al. Apr 2023

Baseline Characteristics Of The North American Prodromal Synucleinopathy Cohort, Jonathan E Elliott, Jennifer Mcleland, Susan R Criswell, Yo-El S Ju, Et Al.

2020-Current year OA Pubs

OBJECTIVE: Rapid eye movement (REM) sleep behavior disorder (RBD) is widely considered a prodromal synucleinopathy, as most with RBD develop overt synucleinopathy within ~10 years. Accordingly, RBD offers an opportunity to test potential treatments at the earliest stages of synucleinopathy. The North American Prodromal Synucleinopathy (NAPS) Consortium has created a multisite RBD participant, primarily clinic-based cohort to better understand characteristics at diagnosis, and in future work, identify predictors of phenoconversion, develop synucleinopathy biomarkers, and enable early stage clinical trial enrollment.

METHODS: Participants ≥18 years of age with overnight polysomnogram-confirmed RBD without Parkinson's disease, dementia, multiple system atrophy, or narcolepsy were …


Charged Multivesicular Body Protein 4b Forms Complexes With Gap Junction Proteins During Lens Fiber Cell Differentiation, Yuefang Zhou, Thomas M Bennett, Thomas W White, Alan Shiels Apr 2023

Charged Multivesicular Body Protein 4b Forms Complexes With Gap Junction Proteins During Lens Fiber Cell Differentiation, Yuefang Zhou, Thomas M Bennett, Thomas W White, Alan Shiels

2020-Current year OA Pubs

Charged multivesicular body protein 4b (CHMP4B) is a core sub-unit of the endosomal sorting complex required for transport III (ESCRT-III) machinery that serves myriad remodeling and scission processes of biological membranes. Mutation of the human CHMP4B gene underlies rare forms of early-onset lens opacities or cataracts, and CHMP4B is required for lens growth and differentiation in mice. Here, we determine the sub-cellular distribution of CHMP4B in the lens and uncover a novel association with gap junction alpha-3 protein (GJA3) or connexin 46 (Cx46) and GJA8 or Cx50. Immunofluorescence confocal microscopy revealed that CHMP4B localized to cell membranes of elongated fiber …


Regulation Of Astrocyte Lipid Metabolism And Apoe Secretion By The Microglial Oxysterol, 25-Hydroxycholesterol, Anil G Cashikar, Danira Toral-Rios, David Timm, Johnathan Romero, Michael Strickland, Justin M Long, Xianlin Han, David M Holtzman, Steven M Paul Apr 2023

Regulation Of Astrocyte Lipid Metabolism And Apoe Secretion By The Microglial Oxysterol, 25-Hydroxycholesterol, Anil G Cashikar, Danira Toral-Rios, David Timm, Johnathan Romero, Michael Strickland, Justin M Long, Xianlin Han, David M Holtzman, Steven M Paul

2020-Current year OA Pubs

Neuroinflammation, a major hallmark of Alzheimer's disease and several other neurological and psychiatric disorders, is often associated with dysregulated cholesterol metabolism. Relative to homeostatic microglia, activated microglia express higher levels of Ch25h, an enzyme that hydroxylates cholesterol to produce 25-hydroxycholesterol (25HC). 25HC is an oxysterol with interesting immune roles stemming from its ability to regulate cholesterol metabolism. Since astrocytes synthesize cholesterol in the brain and transport it to other cells via ApoE-containing lipoproteins, we hypothesized that secreted 25HC from microglia may influence lipid metabolism as well as extracellular ApoE derived from astrocytes. Here, we show that astrocytes take up externally …


The Who Aware (Access, Watch, Reserve) Antibiotic Book And Prevention Of Antimicrobial Resistance, Veronica Zanichelli, Michael Sharland, Bernadette Cappello, Lorenzo Moja, Haileyesus Getahun, Carmem Pessoa-Silva, Hatim Sati, Catharina Van Weezenbeek, Hanan Balkhy, Mariângela Simão, Sumanth Gandra, Benedikt Huttner Apr 2023

The Who Aware (Access, Watch, Reserve) Antibiotic Book And Prevention Of Antimicrobial Resistance, Veronica Zanichelli, Michael Sharland, Bernadette Cappello, Lorenzo Moja, Haileyesus Getahun, Carmem Pessoa-Silva, Hatim Sati, Catharina Van Weezenbeek, Hanan Balkhy, Mariângela Simão, Sumanth Gandra, Benedikt Huttner

2020-Current year OA Pubs

Guidance on the appropriate use of antibiotics for common infections is lacking in many settings. The World Health Organization (WHO) has recently released


Complete Remission Of Widely Metastatic Human Epidermal Growth Factor Receptor 2-Amplified Pancreatic Adenocarcinoma After Precision Immune And Targeted Therapy With Description Of Sequencing And Organoid Correlates, Daniel A King, S Peter Goedegebuure, Xiuli Zhang, Jasreet Hundal, Malachi Griffith, William E Gillanders, Haeseong Park, Et Al. Apr 2023

Complete Remission Of Widely Metastatic Human Epidermal Growth Factor Receptor 2-Amplified Pancreatic Adenocarcinoma After Precision Immune And Targeted Therapy With Description Of Sequencing And Organoid Correlates, Daniel A King, S Peter Goedegebuure, Xiuli Zhang, Jasreet Hundal, Malachi Griffith, William E Gillanders, Haeseong Park, Et Al.

2020-Current year OA Pubs

No abstract provided.