Digital Commons Network^™

Peroxisomal Β-Oxidation Acts As A Sensor For Intracellular Fatty Acids And Regulates Lipolysis, Lianggong Ding, Wenfei Sun, Miroslav Balaz, Anyuan He, Manuel Klug, Stefan Wieland, Robert Caiazzo, Violeta Raverdy, Francois Pattou, Philippe Lefebvre, Irfan J Lodhi, Bart Staels, Markus Heim, Christian Wolfrum

Open Access Publications

To liberate fatty acids (FAs) from intracellular stores, lipolysis is regulated by the activity of the lipases adipose triglyceride lipase (ATGL), hormone-sensitive lipase and monoacylglycerol lipase. Excessive FA release as a result of uncontrolled lipolysis results in lipotoxicity, which can in turn promote the progression of metabolic disorders. However, whether cells can directly sense FAs to maintain cellular lipid homeostasis is unknown. Here we report a sensing mechanism for cellular FAs based on peroxisomal degradation of FAs and coupled with reactive oxygen species (ROS) production, which in turn regulates FA release by modulating lipolysis. Changes in ROS levels are sensed …

Axicabtagene Ciloleucel As Second-Line Therapy For Large B-Cell Lymphoma, Frederick L Locke, Armin Ghobadi, Et Al

Open Access Publications

BACKGROUND: The prognosis of patients with early relapsed or refractory large B-cell lymphoma after the receipt of first-line chemoimmunotherapy is poor.

METHODS: In this international, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with large B-cell lymphoma that was refractory to or had relapsed no more than 12 months after first-line chemoimmunotherapy to receive axicabtagene ciloleucel (axi-cel, an autologous anti-CD19 chimeric antigen receptor T-cell therapy) or standard care (two or three cycles of investigator-selected, protocol-defined chemoimmunotherapy, followed by high-dose chemotherapy with autologous stem-cell transplantation in patients with a response to the chemoimmunotherapy). The primary end point was …

Hedgehog-Interacting Protein Is A Multimodal Antagonist Of Hedgehog Signalling, Samuel C Griffiths, Rebekka A Schwab, Kamel El Omari, Benjamin Bishop, Ellen J Iverson, Tomas Malinauskas, Ramin Dubey, Mingxing Qian, Douglas F Covey, Robert J C Gilbert, Rajat Rohatgi, Christian Siebold

Open Access Publications

Hedgehog (HH) morphogen signalling, crucial for cell growth and tissue patterning in animals, is initiated by the binding of dually lipidated HH ligands to cell surface receptors. Hedgehog-Interacting Protein (HHIP), the only reported secreted inhibitor of Sonic Hedgehog (SHH) signalling, binds directly to SHH with high nanomolar affinity, sequestering SHH. Here, we report the structure of the HHIP N-terminal domain (HHIP-N) in complex with a glycosaminoglycan (GAG). HHIP-N displays a unique bipartite fold with a GAG-binding domain alongside a Cysteine Rich Domain (CRD). We show that HHIP-N is required to convey full HHIP inhibitory function, likely by interacting with the …

Regenerative Responses Of Rabbit Corneal Endothelial Cells To Stimulation By Fibroblast Growth Factor 1 (Fgf1) Derivatives, Tthx1001 And Tthx1114, Jessica Weant, David D Eveleth, Amuthakannan Subramaniam, Jennifer Jenkins-Eveleth, Michael Blaber, Ling Li, David M Ornitz, Asaf Alimardanov, Trevor Broadt, Hui Dong, Vinay Vyas, Xiaoyi Yang, Ralph A Bradshaw

Open Access Publications

Utilising rabbit corneal endothelial cells (CEC) in three different paradigms, two human FGF1 derivatives (TTHX1001 and TTHX1114), engineered to exhibit greater stability, were tested as proliferative agents. Primary CECs and mouse NIH 3T3 cells treated with the two FGF1 derivatives showed equivalent EC

Lyl-1 Regulates Primitive Macrophages And Microglia Development, Shoutang Wang, Deshan Ren, Brahim Arkoun, Anna-Lila Kaushik, Gabriel Matherat, Yann Lécluse, Dominik Filipp, William Vainchenker, Hana Raslova, Isabelle Plo, Isabelle Godin

Open Access Publications

During ontogeny, macrophage populations emerge in the Yolk Sac (YS) via two distinct progenitor waves, prior to hematopoietic stem cell development. Macrophage progenitors from the primitive/"early EMP" and transient-definitive/"late EMP" waves both contribute to various resident primitive macrophage populations in the developing embryonic organs. Identifying factors that modulates early stages of macrophage progenitor development may lead to a better understanding of defective function of specific resident macrophage subsets. Here we show that YS primitive macrophage progenitors express Lyl-1, a bHLH transcription factor related to SCL/Tal-1. Transcriptomic analysis of YS macrophage progenitors indicate that primitive macrophage progenitors present at embryonic day …

Asthma Reduces Glioma Formation By T Cell Decorin-Mediated Inhibition Of Microglia, Jit Chatterjee, Shilpa Sanapala, Olivia Cobb, Alice Bewley, Andrea K Goldstein, Elizabeth Cordell, Xia Ge, Joel R Garbow, Michael J Holtzman, David H Gutmann

Open Access Publications

To elucidate the mechanisms underlying the reduced incidence of brain tumors in children with Neurofibromatosis type 1 (NF1) and asthma, we leverage Nf1 optic pathway glioma (Nf1

Immunosuppression And Outcomes In Adult Patients With De Novo Acute Myeloid Leukemia With Normal Karyotypes, Francesca Ferraro, Christopher A Miller, Keegan A Christensen, Nichole M Helton, Margaret O'Laughlin, Catrina C Fronick, Robert S Fulton, Jessica Kohlschmidt, Ann-Kathrin Eisfeld, Clara D Bloomfield, Sai Mukund Ramakrishnan, Ryan B Day, Lukas D Wartman, Geoffrey L Uy, John S Welch, Matthew J Christopher, Sharon E Heath, Jack D Baty, Matthew J Schuelke, Jacqueline E Payton, David H Spencer, Michael P Rettig, Daniel C Link, Matthew J Walter, Peter Westervelt, John F Dipersio, Timothy J Ley

Open Access Publications

Acute myeloid leukemia (AML) patients rarely have long first remissions (LFRs; >5 y) after standard-of-care chemotherapy, unless classified as favorable risk at presentation. Identification of the mechanisms responsible for long vs. more typical, standard remissions may help to define prognostic determinants for chemotherapy responses. Using exome sequencing, RNA-sequencing, and functional immunologic studies, we characterized 28 normal karyotype (NK)-AML patients with >5 y first remissions after chemotherapy (LFRs) and compared them to a well-matched group of 31 NK-AML patients who relapsed within 2 y (standard first remissions [SFRs]). Our combined analyses indicated that genetic-risk profiling at presentation (as defined by European …

High-Throughput Functional Analysis Of Cftr And Other Apically Localized Proteins In Ipsc-Derived Human Intestinal Organoids, Sunny Xia, Zoltán Bozóky, Michelle Di Paola, Onofrio Laselva, Saumel Ahmadi, Jia Xin Jiang, Amy L Pitstick, Chong Jiang, Daniela Rotin, Christopher N Mayhew, Nicola L Jones, Christine E Bear

Open Access Publications

Induced Pluripotent Stem Cells (iPSCs) can be differentiated into epithelial organoids that recapitulate the relevant context for CFTR and enable testing of therapies targeting Cystic Fibrosis (CF)-causing mutant proteins. However, to date, CF-iPSC-derived organoids have only been used to study pharmacological modulation of mutant CFTR channel activity and not the activity of other disease-relevant membrane protein constituents. In the current work, we describe a high-throughput, fluorescence-based assay of CFTR channel activity in iPSC-derived intestinal organoids and describe how this method can be adapted to study other apical membrane proteins. Specifically, we show how this assay can be employed to study …

Efficacy And Safety Of Avapritinib In Advanced Systemic Mastocytosis: Interim Analysis Of The Phase 2 Pathfinder Trial, Jason Gotlib, Andreas Reiter, Stephen T Oh, Et Al

Open Access Publications

Advanced systemic mastocytosis (AdvSM) is a rare, KIT D816V-driven hematologic neoplasm characterized by mast cell infiltration and shortened survival. We report the results of a prespecified interim analysis of an ongoing pivotal single-arm phase 2 trial (no. NCT03580655 ) of avapritinib, a potent, selective KIT D816V inhibitor administered primarily at a once-daily starting dose of 200 mg in patients with AdvSM (n = 62). The primary endpoint was overall response rate (ORR). Secondary endpoints included mean baseline change in AdvSM-Symptom Assessment Form Total Symptom Score and quality of life, time to response, duration of response, progression-free survival, overall survival, changes …

Access To And Safety Of Covid-19 Convalescent Plasma In The United States Expanded Access Program: A National Registry Study, Jonathon W. Senefeld, Brenda J. Grossman, Et Al

Open Access Publications

BACKGROUND: The United States (US) Expanded Access Program (EAP) to coronavirus disease 2019 (COVID-19) convalescent plasma was initiated in response to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. While randomized clinical trials were in various stages of development and enrollment, there was an urgent need for widespread access to potential therapeutic agents. The objective of this study is to report on the demographic, geographical, and chronological characteristics of patients in the EAP, and key safety metrics following transfusion of COVID-19 convalescent plasma.

METHODS AND FINDINGS: Mayo Clinic served as the central …

Kinetic And Structural Mechanism For Dna Unwinding By A Non-Hexameric Helicase, Sean P. Carney, Wen Ma, Kevin D. Whitley, Haifeng Jia, Timothy M. Lohman, Zaida Luthey-Schulten, Yann R. Chemla

Open Access Publications

No abstract provided.

Trajectory Of Emotion Dysregulation In Positive And Negative Affect Across Childhood Predicts Adolescent Emotion Dysregulation And Overall Functioning, Alecia C. Vogel, Rebecca Tillman, Nourhan M. El-Sayed, Joshua J. Jackson, Susan B. Perlman, Deanna M. Barch, Joan L. Luby

Open Access Publications

No abstract provided.

Compositional Analysis Of Extracellular Aggregates In The Eyes Of Patients With Exfoliation Syndrome And Exfoliation Glaucoma, Alicia De Maria, Keith D Zientek, Larry L David, Phillip A Wilmarth, Anjali M Bhorade, George J Harocopos, Andrew J W Huang, Augustine R Hong, Carla J Siegfried, Linda M Tsai, Arsham Sheybani, Steven Bassnett

Open Access Publications

Purpose: Exfoliation syndrome (XFS) is a condition characterized by the production of insoluble fibrillar aggregates (exfoliation material; XFM) in the eye and elsewhere. Many patients with XFS progress to exfoliation glaucoma (XFG), a significant cause of global blindness. We used quantitative mass spectrometry to analyze the composition of XFM in lens capsule specimens and in aqueous humor (AH) samples from patients with XFS, patients with XFG and unaffected individuals.

Methods: Pieces of lens capsule and samples of AH were obtained with consent from patients undergoing cataract surgery. Tryptic digests of capsule or AH were analyzed by high-performance liquid chromatography-mass spectrometry …

How The Value Of The Environment Controls Persistence In Visual Search, Michael R. Traner, Ethan S. Bromberg-Martin, Ilya E. Monosov

Open Access Publications

Classic foraging theory predicts that humans and animals aim to gain maximum reward per unit time. However, in standard instrumental conditioning tasks individuals adopt an apparently suboptimal strategy: they respond slowly when the expected value is low. This reward-related bias is often explained as reduced motivation in response to low rewards. Here we present evidence this behavior is associated with a complementary increased motivation to search the environment for alternatives. We trained monkeys to search for reward-related visual targets in environments with different values. We found that the reward-related bias scaled with environment value, was consistent with persistent searching after …

Neutrophil Extracellular Trap Inhibition Increases Inflammation, Bacteraemia And Mortality In Murine Necrotizing Enterocolitis, Hala Chaaban, Kathryn Burge, Jeffrey Eckert, Ravi S Keshari, Robert Silasi, Cristina Lupu, Barbara Warner, Marilyn Escobedo, Michael Caplan, Florea Lupu

Open Access Publications

Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease affecting primarily premature infants. The disease is characterized by intestinal inflammation and leucocyte infiltration, often progressing to necrosis, perforation, systemic inflammatory response and death. Neutrophil extracellular traps (NETs), denoting nuclear DNA, histone and antimicrobial protein release, have been suggested to play a role in NEC. This study aimed to determine the role of NETs in NEC and explore the effect of chloramidine, a NET inhibitor, on a murine NEC-like intestinal injury model. Blood and intestinal tissues were collected from infants diagnosed with ≥ Stage II NEC, and levels of nucleosomes and NETs, …

Screening Of Severe Acute Respiratory Syndrome Coronavirus 2 Rna-Dependent Rna Polymerase Inhibitors Using Computational Approach, Poonam Dhankhar, Vikram Dalal, Viney Kumar

Open Access Publications

The detrimental effect of coronavirus disease 2019 (COVID-19) pandemic has manifested itself as a global crisis. Currently, no specific treatment options are available for COVID-19, so therapeutic interventions to tackle the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection must be urgently established. Therefore, cohesive and multidimensional efforts are required to identify new therapies or investigate the efficacy of small molecules and existing drugs against SARS-CoV-2. Since the RNA-dependent RNA Polymerase (RdRP) of SARS-CoV-2 is a promising therapeutic target, this study addresses the identification of antiviral molecules that can specifically target SARS-CoV-2 RdRP. The computational approach of drug development was …

Identification Of Histone Deacetylase Inhibitors With (Arylidene)Aminoxy Scaffold Active In Uveal Melanoma Cell Lines, Susanna Nencetti, Doretta Cuffaro, Elisa Nuti, Lidia Ciccone, Armando Rossello, Marina Fabbi, Flavio Ballante, Gabriella Ortore, Grazia Carbotti, Francesco Campelli, Irene Banti, Rosaria Gangemi, Garland R Marshall, Elisabetta Orlandini

Open Access Publications

Uveal melanoma (UM) represents an aggressive type of cancer and currently, there is no effective treatment for this metastatic disease. In the last years, histone deacetylase inhibitors (HDACIs) have been studied as a possible therapeutic treatment for UM, alone or in association with other chemotherapeutic agents. Here we synthesised a series of new HDACIs based on the SAHA scaffold bearing an (arylidene)aminoxy moiety. Their HDAC inhibitory activity was evaluated on isolated human HDAC1, 3, 6, and 8 by fluorometric assay and their binding mode in the catalytic site of HDACs was studied by molecular docking. The most promising hit was …

Insulin And Glucose Metabolism With Olanzapine And A Combination Of Olanzapine And Samidorphan: Exploratory Phase 1 Results In Healthy Volunteers, Frederico G S Toledo, William F Martin, Linda Morrow, Carine Beysen, Daiva Bajorunas, Ying Jiang, Bernard L Silverman, David Mcdonnell, Mark N Namchuk, John W Newcomer, Christine Graham

Open Access Publications

A combination of olanzapine and samidorphan (OLZ/SAM) received US Food and Drug Administration approval in May 2021 for the treatment of adults with schizophrenia or bipolar I disorder. OLZ/SAM provides the efficacy of olanzapine, while mitigating olanzapine-associated weight gain. This exploratory study characterized the metabolic profile of OLZ/SAM in healthy volunteers to gain mechanistic insights. Volunteers received once-daily oral 10 mg/10 mg OLZ/SAM, 10 mg olanzapine, or placebo for 21 days. Assessments included insulin sensitivity during an oral glucose tolerance test (OGTT), hyperinsulinemic-euglycemic clamp, other measures of glucose/lipid metabolism, and adverse event (AE) monitoring. Treatment effects were estimated with analysis …

Identification Of Disease-Linked Hyperactivating Mutations In Ube3a Through Large-Scale Functional Variant Analysis, Kellan P Weston, Xiaoyi Gao, Jinghan Zhao, Kwang-Soo Kim, Susan E Maloney, Jill Gotoff, Sumit Parikh, Yen-Chen Leu, Kuen-Phon Wu, Marwan Shinawi, Joshua P Steimel, Joseph S Harrison, Jason J Yi

Open Access Publications

The mechanisms that underlie the extensive phenotypic diversity in genetic disorders are poorly understood. Here, we develop a large-scale assay to characterize the functional valence (gain or loss-of-function) of missense variants identified in UBE3A, the gene whose loss-of-function causes the neurodevelopmental disorder Angelman syndrome. We identify numerous gain-of-function variants including a hyperactivating Q588E mutation that strikingly increases UBE3A activity above wild-type UBE3A levels. Mice carrying the Q588E mutation exhibit aberrant early-life motor and communication deficits, and individuals possessing hyperactivating UBE3A variants exhibit affected phenotypes that are distinguishable from Angelman syndrome. Additional structure-function analysis reveals that Q588 forms a regulatory site …

Visual Prototypes In The Ventral Stream Are Attuned To Complexity And Gaze Behavior, Olivia Rose, James Johnson, Binxu Wang, Carlos R Ponce

Open Access Publications

Early theories of efficient coding suggested the visual system could compress the world by learning to represent features where information was concentrated, such as contours. This view was validated by the discovery that neurons in posterior visual cortex respond to edges and curvature. Still, it remains unclear what other information-rich features are encoded by neurons in more anterior cortical regions (e.g., inferotemporal cortex). Here, we use a generative deep neural network to synthesize images guided by neuronal responses from across the visuocortical hierarchy, using floating microelectrode arrays in areas V1, V4 and inferotemporal cortex of two macaque monkeys. We hypothesize …

Dasatinib And Dexamethasone Followed By Hematopoietic Cell Transplantation For Adults With Ph-Positive All, Matthew J. Wieduwilt, Geoffrey L. Uy, Et Al

Open Access Publications

No abstract provided.

Optimization Of Non-Coding Regions For A Non-Modified Mrna Covid-19 Vaccine, Makda S Gebre, Susanne Rauch, Adrianus C M Boon, Et Al

Open Access Publications

The CVnCoV (CureVac) mRNA vaccine for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was recently evaluated in a phase 2b/3 efficacy trial in humans

Dual Lactate Clearance In The Viability Assessment Of Livers Donated After Circulatory Death With Ex Situ Normothermic Machine Perfusion, Min Xu, Fangyu Zhou, Ola Ahmed, Lucy V Randle, Jun-Kyu Shin, Yuehui Zhu, Gundumi A Upadhya, Kathleen Byrnes, Brian Wong, Jae-Sung Kim, Yiing Lin, William C Chapman

Open Access Publications

Perfusate lactate clearance (LC) is considered one of the useful indicators of liver viability assessment during normothermic machine perfusion (NMP); however, the applicable scope and potential mechanisms of LC remain poorly defined in the setting of liver donation after circulatory death.

Methods: The ex situ NMP of end-ischemic human livers was performed using the OrganOx Metra device. We further studied the extracellular signal-regulated kinases (phospho-extracellular signal-regulated kinase1/2 [pERK1/2]) pathway and several clinical parameters of these livers with successful LC (sLC, n = 5) compared with non-sLC (nLC, n = 5) in the perfusate (<2.2 mmol/L at 2 h, n = 5, rapid retrieval without normothermic regional perfusion).

Results: We found the pERK1/2 level …

Angiotensin Receptor-Neprilysin Inhibition In Acute Myocardial Infarction, Marc A Pfeffer, Douglas L Mann, Et Al

Open Access Publications

BACKGROUND: In patients with symptomatic heart failure, sacubitril-valsartan has been found to reduce the risk of hospitalization and death from cardiovascular causes more effectively than an angiotensin-converting-enzyme inhibitor. Trials comparing the effects of these drugs in patients with acute myocardial infarction have been lacking.

METHODS: We randomly assigned patients with myocardial infarction complicated by a reduced left ventricular ejection fraction, pulmonary congestion, or both to receive either sacubitril-valsartan (97 mg of sacubitril and 103 mg of valsartan twice daily) or ramipril (5 mg twice daily) in addition to recommended therapy. The primary outcome was death from cardiovascular causes or incident …

Estradiol Protects Against Noise-Induced Hearing Loss And Modulates Auditory Physiology In Female Mice, Benjamine Shuster, Ryan Casserly, Erika Lipford, Rafal Olszewski, Beatrice Milon, Shaun Viechweg, Kanisa Davidson, Jennifer Enoch, Mark Mcmurray, Mark A. Rutherford, Kevin K. Ohlemiller, Michael Hoa, Didier A. Depireux, Jessica A. Mong, Ronna Hertzano

Open Access Publications

No abstract provided.

Matched Cohort Study Of Germline Brca Mutation Carriers With Triple Negative Breast Cancer In Brightness, Otto Metzger-Filho, Katharine Collier, Sarah Asad, Mark Watson, Et Al

Open Access Publications

No abstract provided.

Cognitive Deficits And Impaired Hippocampal Long-Term Potentiation In K Atp-Induced Dend Syndrome, Shaul Yahil, David F Wozniak, Zihan Yan, Steven Mennerick, Maria S Remedi

Open Access Publications

ATP-sensitive potassium (K

Using Postmarket Surveillance To Assess Safety-Related Events In A Digital Rehabilitation App (Kaia App): Observational Study, Deeptee Jain, Kevin Norman, Zachary Werner, Bar Makovoz, Turner Baker, Stephan Huber

Open Access Publications

BACKGROUND: Low back pain (LBP) affects nearly 4 out of 5 individuals during their lifetime and is the leading cause of disability globally. Digital therapeutics are emerging as effective treatment options for individuals experiencing LBP. Despite the growth of evidence demonstrating the benefits of these therapeutics in reducing LBP and improving functional outcomes, little data has been systematically collected on their safety profiles.

OBJECTIVE: This study aims to evaluate the safety profile of a multidisciplinary digital therapeutic for LBP, the Kaia App, by performing a comprehensive assessment of reported adverse events (AEs) by users as captured by a standardized process …

Synaptic Zn 2+ Potentiates The Effects Of Cocaine On Striatal Dopamine Neurotransmission And Behavior, Juan L. Gomez, Marco Pignatelli, Et Al

Open Access Publications

No abstract provided.

Staphylococcus Aureus Injection Drug Use-Associated Bloodstream Infections Are Propagated By Community Outbreaks Of Diverse Lineages, Laura R Marks, Juan J Calix, John A Wildenthal, Meghan A Wallace, Sanjam S Sawhney, Eric M Ransom, Michael J Durkin, Jeffrey P Henderson, Carey-Ann D Burnham, Gautam Dantas

Open Access Publications

Background: The ongoing injection drug use (IDU) crisis in the United States has been complicated by an emerging epidemic of

Methods: We performed a case-control study comparing

Results: Here we show that patients with IDU-BSI experience longer durations of bacteremia and have lower medical therapy completion rates. In phylogenetic analyses, 45/154 and 1/91 contemporaneous IDU-BSI and non-IDU BSI staphylococcal isolates, respectively, group into multiple, unique clonal clusters, revealing that pathogen community transmission distinctively spurs IDU-BSI. Lastly, multiple

Conclusions: We identify clonal expansion of multiple