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Outcomes Of Rescue Endovascular Treatment Of Emergent Large Vessel Occlusion In Patients With Underlying Intracranial Atherosclerosis: Insights From Star, Sami Al Kasab, Joshua Osbun, Et Al

Open Access Publications

Background Some emergent large vessel occlusions (ELVOs) are refractory to reperfusion because of underlying intracranial atherosclerosis (ICAS), often requiring rescue therapy (RT) with balloon angioplasty, stenting, or both. In this study, we investigate the safety, efficacy, and long-term outcomes of RT in the setting of mechanical thrombectomy for ICAS-related ELVO. Methods and Results We queried the databases of 10 thrombectomy-capable centers in North America and Europe included in STAR (Stroke Thrombectomy and Aneurysm Registry). Patients with ELVO who underwent ICAS-related RT were included. A matched sample was produced for variables of age, admission National Institute of Health Stroke Scale, Alberta …

Probing The Signaling Requirements For Naive Human Pluripotency By High-Throughput Chemical Screening, Shafqat A Khan, Kyoung-Mi Park, Laura A Fischer, Chen Dong, Tenzin Lungjangwa, Marta Jimenez, Dominick Casalena, Brian Chew, Sabine Dietmann, Douglas S Auld, Rudolf Jaenisch, Thorold W Theunissen

Open Access Publications

Naive human embryonic stem cells (hESCs) have been isolated that more closely resemble the pre-implantation epiblast compared to conventional "primed" hESCs, but the signaling principles underlying these discrete stem cell states remain incompletely understood. Here, we describe the results from a high-throughput screen using ∼3,000 well-annotated compounds to identify essential signaling requirements for naive human pluripotency. We report that MEK1/2 inhibitors can be replaced during maintenance of naive human pluripotency by inhibitors targeting either upstream (FGFR, RAF) or downstream (ERK1/2) kinases. Naive hESCs maintained under these alternative conditions display elevated levels of ERK phosphorylation but retain genome-wide DNA hypomethylation and …

A Phase 2a Randomized Clinical Trial Of Intravenous Vedolizumab For The Treatment Of Steroid-Refractory Intestinal Acute Graft-Versus-Host Disease, Yngvar Fløisand, Mark A Schroeder, Patrice Chevallier, Dominik Selleslag, Steven Devine, Anne S Renteria, Mohamad Mohty, Ibrahim Yakoub-Agha, Chunlin Chen, Andrejus Parfionovas, Syed Quadri, Johan Jansson, Mona Akbari, Yi-Bin Chen

Open Access Publications

Steroid-refractory (SR) acute graft-versus-host disease (aGvHD) remains a significant complication after allogeneic hematopoietic cell transplantation. Systemic corticosteroids are first-line therapy for aGvHD, but apart from ruxolitinib, there are no approved treatments for SR aGvHD. Vedolizumab is approved for treatment of ulcerative colitis and Crohn's disease, and may be effective for treatment of SR intestinal aGvHD. We conducted a phase 2a trial (NCT02993783) to evaluate the clinical efficacy, tolerability, and safety of vedolizumab 300 and 600 mg for SR intestinal aGvHD. This study was terminated before full enrollment was completed because early results failed to demonstrate positive proof-of-concept in efficacy. Before …

Balancing Serendipity And Reproducibility: Pluripotent Stem Cells As Experimental Systems For Intellectual And Developmental Disorders, Nickesha C Anderson, Pin-Fang Chen, Kesavan Meganathan, Wardiya Afshar Saber, Andrew J Petersen, Anita Bhattacharyya, Kristen L Kroll, Mustafa Sahin, Cross-Iddrc Human Stem Cell Working Group

Open Access Publications

Reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) and their differentiation into neural lineages is a revolutionary experimental system for studying neurological disorders, including intellectual and developmental disabilities (IDDs). However, issues related to variability and reproducibility have hindered translating preclinical findings into drug discovery. Here, we identify areas for improvement by conducting a comprehensive review of 58 research articles that utilized iPSC-derived neural cells to investigate genetically defined IDDs. Based upon these findings, we propose recommendations for best practices that can be adopted by research scientists as well as journal editors.

Soluble P-Tau217 Reflects Amyloid And Tau Pathology And Mediates The Association Of Amyloid With Tau, Niklas Mattsson-Carlgren, Shorena Janelidze, Randall J Bateman, Ruben Smith, Erik Stomrud, Geidy E Serrano, Eric M Reiman, Sebastian Palmqvist, Jeffrey L Dage, Thomas G Beach, Oskar Hansson

Open Access Publications

Alzheimer's disease is characterized by β-amyloid plaques and tau tangles. Plasma levels of phospho-tau217 (P-tau217) accurately differentiate Alzheimer's disease dementia from other dementias, but it is unclear to what degree this reflects β-amyloid plaque accumulation, tau tangle accumulation, or both. In a cohort with post-mortem neuropathological data (N = 88), both plaque and tangle density contributed independently to higher P-tau217, but P-tau217 was not elevated in patients with non-Alzheimer's disease tauopathies (N = 9). Several findings were replicated in a cohort with PET imaging ("BioFINDER-2", N = 426), where β-amyloid and tau PET were independently associated with P-tau217. P-tau217 concentrations …

Rnf20 And Rnf40 Regulate Vitamin D Receptor-Dependent Signaling In Inflammatory Bowel Disease, Robyn Laura Kosinsky, Maria Zerche, Rodney D Newberry, Et Al

Open Access Publications

Despite the identification of several genetic factors linked to increased susceptibility to inflammatory bowel disease (IBD), underlying molecular mechanisms remain to be elucidated in detail. The ubiquitin ligases RNF20 and RNF40 mediate the monoubiquitination of histone H2B at lysine 120 (H2Bub1) and were shown to play context-dependent roles in the development of inflammation. Here, we aimed to examine the function of the RNF20/RNF40/H2Bub1 axis in intestinal inflammation in IBD patients and mouse models. For this purpose, intestinal sections from IBD patients were immunohistochemically stained for H2Bub1. Rnf20 or Rnf40 were conditionally deleted in the mouse intestine and mice were monitored …

Reliance On Cox10 And Oxidative Metabolism For Antigen-Specific Nk Cell Expansion, Annelise Y Mah-Som, Molly P Keppel, Joshua M Tobin, Ana Kolicheski, Nermina Saucier, Veronika Sexl, Anthony R French, Julia A Wagner, Todd A Fehniger, Megan A Cooper

Open Access Publications

Natural killer (NK) cell effector functions are dependent on metabolic regulation of cellular function; however, less is known about in vivo metabolic pathways required for NK cell antiviral function. Mice with an inducible NK-specific deletion of Cox10, which encodes a component of electron transport chain complex IV, were generated to investigate the role of oxidative phosphorylation in NK cells during murine cytomegalovirus (MCMV) infection. Ncr1-Cox10

Restless Legs Syndrome Shows Increased Silent Postmortem Cerebral Microvascular Disease With Gliosis, Arthur S Walters, Paisit Paueksakon, Charles H Adler, Michael Moussouttas, Leonard B Weinstock, Karen Spruyt, Kanika Bagai

Open Access Publications

Background Patients with restless legs syndrome (RLS) have increased silent microvascular disease by magnetic resonance imaging. However, there has been no previous autopsy confirmation of these magnetic resonance imaging findings. RLS is also frequently associated with inflammatory and immunologically mediated medical disorders. The postmortem cortex in patients with RLS was therefore evaluated for evidence of microvascular and immunological changes. Methods and Results Ten microvascular injury samples of precentral gyrus in 5 patients with RLS (3 men, 2 women; mean age, 81 years) and 9 controls (2 men, 7 women; mean age, 90 years) were studied by hematoxylin and eosin stains …

Examination Of A Blood-Brain Barrier Targeting Β-Galactosidase-Monoclonal Antibody Fusion Protein In A Murine Model Of Gm1-Gangliosidosis, Michael J Przybilla, Christine Stewart, Timothy W Carlson, Li Ou, Brenda L Koniar, Rohini Sidhu, Pamela J Kell, Xuntian Jiang, Jeanine R Jarnes, M Gerard O'Sullivan, Chester B Whitley

Open Access Publications

GM1-gangliosidosis is a lysosomal disease resulting from a deficiency in the hydrolase β-galactosidase (β-gal) and subsequent accumulation of gangliosides, primarily in neuronal tissue, leading to progressive neurological deterioration and eventually early death. Lysosomal diseases with neurological involvement have limited non-invasive therapies due to the inability of lysosomal enzymes to cross the blood-brain barrier (BBB). A novel fusion enzyme, labeled mTfR-GLB1, was designed to act as a ferry across the BBB by fusing β-gal to the mouse monoclonal antibody against the mouse transferrin receptor and tested in a murine model of GM1-gangliosidosis (β-gal

Placental Pathology In An Unsuspected Case Of Mucolipidosis Type Ii With Secondary Hyperparathyroidism In A Premature Infant, Parith Wongkittichote, Garland Michael Upchurch, Louis P Dehner, Timothy Wood, Jorge L Granadillo

Open Access Publications

Mucolipidosis type II (MLII, MIM 252500) is a lysosomal storage disorders caused by defects in

N-Cadherin In Osteolineage Cells Modulates Stromal Support Of Tumor Growth, Francesca Fontana, Jingyu Xiang, Xinming Su, Eric Tycksen, Rachel Nassau, Gregory Fox, Giulia Leanza, Katherine Weilbaecher, Roberto Civitelli

Open Access Publications

Tumor growth and metastases are dependent on interactions between cancer cells and the local environment. Expression of the cell-cell adhesion molecule N-cadherin (Ncad) is associated with highly aggressive cancers, and its expression by osteogenic cells has been proposed to provide a molecular "dock" for disseminated tumor cells to establish in pre-metastatic niches within the bone. To test this biologic model, we conditionally deleted the Ncad gene (

Clinical Implications Of Estimated Glomerular Filtration Rate Dip Following Sodium-Glucose Cotransporter-2 Inhibitor Initiation On Cardiovascular And Kidney Outcomes, Yan Xie, Benjamin Bowe, Andrew K Gibson, Janet B Mcgill, Geetha Maddukuri, Ziyad Al-Aly

Open Access Publications

Background The frequency of the initial short-term decline in estimated glomerular filtration rate (eGFR), eGFR dip, following initiation of sodium-glucose cotransporter-2 inhibitors (SGLT2i) and its clinical implications in real-world practice are not clear. Methods and Results We built a cohort of 36 638 new users of SGLT2i and 209 025 new users of other antihyperglycemics. Inverse probability weighting was used to estimate the excess rate of eGFR dip, risk of the composite cardiovascular outcome of nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, or all-cause mortality, and risk of the composite kidney outcome of eGFR decline >50%, end-stage kidney …

Cardiovascular Adverse Events Associated With Braf Versus Braf/Mek Inhibitor: Cross-Sectional And Longitudinal Analysis Using Two Large National Registries, Avirup Guha, Prantesh Jain, Michael G Fradley, Daniel Lenihan, Jahir M Gutierrez, Chhavi Jain, Marcos De Lima, Jill S Barnholtz-Sloan, Guilherme H Oliveira, Afshin Dowlati, Sadeer Al-Kindi

Open Access Publications

BACKGROUND: Cardiovascular adverse events (CVAEs) associated with BRAF inhibitors alone versus combination BRAF/MEK inhibitors are not fully understood.

METHODS: This study included all adult patients who received BRAF inhibitors (vemurafenib, dabrafenib, encorafenib) or combinations BRAF/MEK inhibitors (vemurafenib/cobimetinib; dabrafenib/trametinib; encorafenib/binimetinib). We utilized the cross-sectional FDA's Adverse Events Reporting System (FAERS) and longitudinal Truven Health Analytics/IBM MarketScan database from 2011 to 2018. Various CVAEs, including arterial hypertension, heart failure (HF), and venous thromboembolism (VTE), were studied using adjusted regression techniques.

RESULTS: In FAERS, 7752 AEs were reported (40% BRAF and 60% BRAF/MEK). Median age was 60 (IQR 49-69) years with 45% females …

Cardiac Safety Of Trabectedin Monotherapy Or In Combination With Pegylated Liposomal Doxorubicin In Patients With Sarcomas And Ovarian Cancer, Robin L Jones, Thomas J Herzog, Shreyaskumar R Patel, Margaret Von Mehren, Scott M Schuetze, Brian A Van Tine, Robert L Coleman, Roland Knoblauch, Spyros Triantos, Peter Hu, Waleed Shalaby, Tracy Mcgowan, Bradley J Monk, George D Demetri

Open Access Publications

BACKGROUND: As with other alkylating agents, cardiac dysfunction can occur with trabectedin therapy for advanced soft tissue sarcomas (STS) or recurrent ovarian cancer (ROC) where treatment options for advanced disease are still limited. Cardiac safety for trabectedin monotherapy (T) for STS or in combination with pegylated liposomal doxorubicin (T+PLD) for ROC was evaluated in this retrospective postmarketing regulatory commitment.

METHODS: Patient data for multiple cardiac-related treatment-emergent adverse events (cTEAEs) were evaluated in pooled analyses of ten phase 2 trials, one phase 3 trial in STS (n = 982), and two phase 3 trials in ROC (n = 1231).

RESULTS: Multivariate …

Cervical Cancer Screening Outcomes In Zambia, 2010-19: A Cohort Study, Jake M Pry, Albert Manasyan, Sharon Kapambwe, Katayoun Taghavi, Miquel Duran-Frigola, Mulindi Mwanahamuntu, Izukanji Sikazwe, Jane Matambo, Jack Mubita, Kennedy Lishimpi, Kennedy Malama, Carolyn Bolton Moore

Open Access Publications

BACKGROUND: Globally, cervical cancer is the fourth leading cause of cancer-related death among women. Poor uptake of screening services contributes to the high mortality. We aimed to examine screening frequency, predictors of screening results, and patterns of sensitisation strategies by age group in a large, programmatic cohort.

METHODS: We did a cohort study including 11 government health facilities in Lusaka, Zambia, in which we reviewed routine programmatic data collected through the Cervical Cancer Prevention Program in Zambia (CCPPZ). Participants who underwent cervical cancer screening in one of the participating study sites were considered for study inclusion if they had a …

Sleep Drive Reconfigures Wake-Promoting Clock Circuitry To Regulate Adaptive Behavior, Markus K. Klose, Paul J. Shaw

Open Access Publications

Circadian rhythms help animals synchronize motivated behaviors to match environmental demands. Recent evidence indicates that clock neurons influence the timing of behavior by differentially altering the activity of a distributed network of downstream neurons. Downstream circuits can be remodeled by Hebbian plasticity, synaptic scaling, and, under some circumstances, activity-dependent addition of cell surface receptors; the role of this receptor respecification phenomena is not well studied. We demonstrate that high sleep pressure quickly reprograms the wake-promoting large ventrolateral clock neurons to express the pigment dispersing factor receptor (PDFR). The addition of this signaling input into the circuit is associated with increased …

Epidemic Preparedness: Prenatal Zika Virus Screening During The Next Epidemic, Luxi Qiao, Celina M Turchi Martelli, Amber I Raja, Nuria Sanchez Clemente, Thalia Velho Barreto De Araùjo, Ricardo Arraes De Alencar Ximenes, Demócrito De Barros Miranda-Filho, Anna Ramond, Elizabeth B Brickley

Open Access Publications

Zika virus (ZIKV) is a vectorborne infectious agent of global public health significance due to its potential to cause severe teratogenic outcomes. The question of whether health systems should consider adopting screening programmes for ZIKV infections during pregnancy warrants consideration. In this analysis, we apply the Wilson-Jungner framework to appraise the potential utility of a prenatal ZIKV screening programme, outline potential screening strategies within the case-finding pathway, and consider other epidemiological factors that may influence the planning of such a screening programme. Our evaluation of a potential prenatal ZIKV screening programme highlights factors affirming its usefulness, including the importance of …

Longitudinal Data Reveal Strong Genetic And Weak Non-Genetic Components Of Ethnicity-Dependent Blood Dna Methylation Levels, Chris Mckennan, Katherine Naughton, Catherine Stanhope, Meyer Kattan, George T O'Connor, Megan T Sandel, Cynthia M Visness, Robert A Wood, Leonard B Bacharier, Avraham Beigelman, Stephanie Lovinsky-Desir, Alkis Togias, James E Gern, Dan Nicolae, Carole Ober

Open Access Publications

Epigenetic architecture is influenced by genetic and environmental factors, but little is known about their relative contributions or longitudinal dynamics. Here, we studied DNA methylation (DNAm) at over 750,000 CpG sites in mononuclear blood cells collected at birth and age 7 from 196 children of primarily self-reported Black and Hispanic ethnicities to study race-associated DNAm patterns. We developed a novel Bayesian method for high-dimensional longitudinal data and showed that race-associated DNAm patterns at birth and age 7 are nearly identical. Additionally, we estimated that up to 51% of all self-reported race-associated CpGs had race-dependent DNAm levels that were mediated through …

A Cardiac Rehabilitation Program For Breast Cancer Survivors: A Feasibility Study, Filadelfiya Zvinovski, Julie A Stephens, Bhuvaneswari Ramaswamy, Raquel E Reinbolt, Anne M Noonan, Jeffrey Bryan Vandeusen, Robert Wesolowski, Daniel G Stover, Nicole Olivia Williams, Sagar D Sardesai, Laxmi Mehta, Randi Foraker, Martha Gulati, Maryam Lustberg, Allison M Quick

Open Access Publications

Purpose: The purpose of this study was to determine the feasibility and preliminary efficacy of a cardiac rehabilitation (CR) intervention in the breast cancer population.

Methods: This single-arm feasibility study evaluated a 14-week CR intervention program in breast cancer survivors. Feasibility was defined as completion of at least 30/36 sessions of the program without serious adverse events (SAE) in 80% of patients. Secondary endpoints included the change in VO2 max, cardiovascular disease (CVD) risk factors, Duke Activity Secondary Index (DASI), Brief Fatigue Inventory (BFI), and QLQ-C30. All outcomes were reported as mean change and compared using paired

Results: A total …

A Sustained Type I Ifn-Neutrophil-Il-18 Axis Drives Pathology During Mucosal Viral Infection, Tania Lebratti, Ying Shiang Lim, Adjoa Cofie, Prabhakar Andhey, Xiaoping Jiang, Jason Scott, Maria Rita Fabbrizi, Ayşe Naz Ozantürk, Christine Pham, Regina Clemens, Maxim Artyomov, Mary Dinauer, Haina Shin

Open Access Publications

Neutrophil responses against pathogens must be balanced between protection and immunopathology. Factors that determine these outcomes are not well-understood. In a mouse model of genital herpes simplex virus-2 (HSV-2) infection, which results in severe genital inflammation, antibody-mediated neutrophil depletion reduced disease. Comparative single-cell RNA-sequencing analysis of vaginal cells against a model of genital HSV-1 infection, which results in mild inflammation, demonstrated sustained expression of interferon-stimulated genes (ISGs) only after HSV-2 infection primarily within the neutrophil population. Both therapeutic blockade of IFNα/β receptor 1 (IFNAR1) and genetic deletion of IFNAR1 in neutrophils concomitantly decreased HSV-2 genital disease severity and vaginal IL-18 …

Spontaneous Neural Synchrony Links Intrinsic Spinal Sensory And Motor Networks During Unconsciousness, Jacob Graves Mcpherson, Maria F. Bandres

Open Access Publications

Non-random functional connectivity during unconsciousness is a defining feature of supraspinal networks. However, its generalizability to intrinsic spinal networks remains incompletely understood. Previously, Barry et al., 2014 used fMRI to reveal bilateral resting state functional connectivity within sensory-dominant and, separately, motor-dominant regions of the spinal cord. Here, we record spike trains from large populations of spinal interneurons in vivo in rats and demonstrate that spontaneous functional connectivity also links sensory- and motor-dominant regions during unconsciousness. The spatiotemporal patterns of connectivity could not be explained by latent afferent activity or by populations of interconnected neurons spiking randomly. We also document connection …

Cellular, Circuit And Transcriptional Framework For Modulation Of Itch In The Central Amygdala, Vijay K. Samineni, Jose G. Grajales-Reyes, Gary E. Grajales-Reyes, Eric Tycksen, Bryan A. Copits, Christian Pedersen, Edem S. Ankudey, Julian N. Sackey, Sienna B. Sewell, Michael R. Bruchas, Robert W. Gereau

Open Access Publications

Itch is an unpleasant sensation that elicits robust scratching and aversive experience. However, the identity of the cells and neural circuits that organize this information remains elusive. Here, we show the necessity and sufficiency of chloroquine-activated neurons in the central amygdala (CeA) for both itch sensation and associated aversion. Further, we show that chloroquine-activated CeA neurons play important roles in itch-related comorbidities, including anxiety-like behaviors, but not in some aversive and appetitive behaviors previously ascribed to CeA neurons. RNA-sequencing of chloroquine-activated CeA neurons identified several differentially expressed genes as well as potential key signaling pathways in regulating pruritis. Finally, viral …

Cell-Autonomous Retinoic Acid Receptor Signaling Has Stage-Specific Effects On Mouse Enteric Nervous System, Tao Gao, Elizabeth C. Wright-Jin, Rajarshi Sengupta, Jessica B. Anderson, Robert O Heuckeroth

Open Access Publications

Retinoic acid (RA) signaling is essential for enteric nervous system (ENS) development, since vitamin A deficiency or mutations in RA signaling profoundly reduce bowel colonization by ENS precursors. These RA effects could occur because of RA activity within the ENS lineage or via RA activity in other cell types. To define cell-autonomous roles for retinoid signaling within the ENS lineage at distinct developmental time points, we activated a potent floxed dominant-negative RA receptor α (RarαDN) in the ENS using diverse CRE recombinase-expressing mouse lines. This strategy enabled us to block RA signaling at premigratory, migratory, and postmigratory stages for ENS …

Common Dna Methylation Dynamics In Endometriod Adenocarcinoma And Glioblastoma Suggest Universal Epigenomic Alterations In Tumorigenesis, Jennifer A Karlow, Benpeng Miao, Xiaoyun Xing, Ting Wang, Bo Zhang

Open Access Publications

Trends in altered DNA methylation have been defined across human cancers, revealing global loss of methylation (hypomethylation) and focal gain of methylation (hypermethylation) as frequent cancer hallmarks. Although many cancers share these trends, little is known about the specific differences in DNA methylation changes across cancer types, particularly outside of promoters. Here, we present a comprehensive comparison of DNA methylation changes between two distinct cancers, endometrioid adenocarcinoma (EAC) and glioblastoma multiforme (GBM), to elucidate common rules of methylation dysregulation and changes unique to cancers derived from specific cells. Both cancers exhibit significant changes in methylation over regulatory elements. Notably, hypermethylated …

Phenotypic And Genomic Profiling Of Staphylococcus Argenteus In Canada And The United States And Recommendations For Clinical Result Reporting, Alireza Eshaghi, Carl Bommersbach, Sandra Zittermann, C A Burnham, Robin Patel, Audrey N Schuetz, Samir N Patel, Julianne V Kus

Open Access Publications

No abstract provided.

Experience With Liposomal Amphotericin B In Outpatient Parenteral Antimicrobial Therapy, Yvonne J Burnett, Andrej Spec, Mohamed M Ahmed, William G Powderly, Yasir Hamad

Open Access Publications

Outpatient parenteral antimicrobial therapy (OPAT) is a safe, effective, and convenient treatment strategy for patients receiving intravenous antimicrobials in the outpatient setting; however, data are limited describing the use and safety of liposomal amphotericin B (L-AMB). Records of patients receiving L-AMB OPAT between 1/1/2015 and 7/31/2018 were retrospectively reviewed. The primary objective was to describe the OPAT patient population discharged on L-AMB and evaluate factors associated with readmission and adverse events (AEs). Analysis was performed to evaluate for predictors of worse outcomes. Forty-two patients (67% male, median age 50 years) were identified, most of whom were treated for histoplasmosis. The …

Value Cmr: Towards A Comprehensive, Rapid, Cost-Effective Cardiovascular Magnetic Resonance Imaging, El-Sayed H Ibrahim, Luba Frank, Dhiraj Baruah, V Emre Arpinar, Andrew S Nencka, Kevin M Koch, L Tugan Muftuler, Orhan Unal, Jadranka Stojanovska, Jason C Rubenstein, Sherry-Ann Brown, John Charlson, Elizabeth M Gore, Carmen Bergom

Open Access Publications

Cardiac magnetic resonance imaging (CMR) is considered the gold standard for measuring cardiac function. Further, in a single CMR exam, information about cardiac structure, tissue composition, and blood flow could be obtained. Nevertheless, CMR is underutilized due to long scanning times, the need for multiple breath-holds, use of a contrast agent, and relatively high cost. In this work, we propose a rapid, comprehensive, contrast-free CMR exam that does not require repeated breath-holds, based on recent developments in imaging sequences. Time-consuming conventional sequences have been replaced by advanced sequences in the proposed CMR exam. Specifically, conventional 2D cine and phase-contrast (PC) …

A Genetic Screen For Regulators Of Muscle Morphogenesis In Drosophila, Tiffany Ou, Gary Huang, Beth Wilson, Paul Gontarz, James B Skeath, Aaron N Johnson

Open Access Publications

The mechanisms that determine the final topology of skeletal muscles remain largely unknown. We have been developing Drosophila body wall musculature as a model to identify and characterize the pathways that control muscle size, shape, and orientation during embryogenesis (Johnson et al., 2013; Williams et al., 2015; Yang et al., 2020a; Yang et al., 2020b). Our working model argues muscle morphogenesis is regulated by (1) extracellular guidance cues that direct muscle cells toward muscle attachment sites, and (2) contact dependent interactions between muscles and tendon cells. While we have identified several pathways that regulate muscle morphogenesis, our understanding is far …

Bundle-Specific Associations Between White Matter Microstructure And Aβ And Tau Pathology In Preclinical Alzheimer's Disease, Alexa Pichet Binette, Tammie Benzinger, John Morris, Randall Bateman, Et Al

Open Access Publications

Beta-amyloid (Aβ) and tau proteins, the pathological hallmarks of Alzheimer's disease (AD), are believed to spread through connected regions of the brain. Combining diffusion imaging and positron emission tomography, we investigated associations between white matter microstructure specifically in bundles connecting regions where Aβ or tau accumulates and pathology. We focused on free-water-corrected diffusion measures in the anterior cingulum, posterior cingulum, and uncinate fasciculus in cognitively normal older adults at risk of sporadic AD and presymptomatic mutation carriers of autosomal dominant AD. In Aβ-positive or tau-positive groups, lower tissue fractional anisotropy and higher mean diffusivity related to greater Aβ and tau …

Transferrable Protection By Gut Microbes Against Sting-Associated Lung Disease, Derek J Platt, Dylan Lawrence, Rachel Rodgers, Lawrence Schriefer, Wei Qian, Cathrine A Miner, Amber M Menos, Elizabeth A Kennedy, Stefan T Peterson, W Alexander Stinson, Megan T Baldridge, Jonathan J Miner

Open Access Publications

STING modulates immunity by responding to bacterial and endogenous cyclic dinucleotides (CDNs). Humans and mice with STING gain-of-function mutations develop a syndrome known as STING-associated vasculopathy with onset in infancy (SAVI), which is characterized by inflammatory or fibrosing lung disease. We hypothesized that hyperresponsiveness of gain-of-function STING to bacterial CDNs might explain autoinflammatory lung disease in SAVI mice. We report that depletion of gut microbes with oral antibiotics (vancomycin, neomycin, and ampicillin [VNA]) nearly eliminates lung disease in SAVI mice, implying that gut microbes might promote STING-associated autoinflammation. However, we show that germ-free SAVI mice still develop severe autoinflammatory disease …