Digital Commons Network^™

Trial Of Spesolimab For Generalized Pustular Psoriasis, Hervé Bachelez, Milan J Anadkat, Et Al

Open Access Publications

BACKGROUND: Generalized pustular psoriasis (GPP) is a rare, life-threatening, inflammatory skin disease characterized by widespread eruption of sterile pustules. Interleukin-36 signaling is involved in the pathogenesis of this disorder. Spesolimab, a humanized anti-interleukin-36 receptor monoclonal antibody, is being studied for the treatment of GPP flares.

METHODS: In a phase 2 trial, we randomly assigned patients with a GPP flare in a 2:1 ratio to receive a single 900-mg intravenous dose of spesolimab or placebo. Patients in both groups could receive an open-label dose of spesolimab on day 8, an open-label dose of spesolimab as a rescue medication after day 8, …

Rotavirus Nsp1 Contributes To Intestinal Viral Replication, Pathogenesis, And Transmission, Gaopeng Hou, Qiru Zeng, Jelle Matthijnssens, Harry B Greenberg, Siyuan Ding

Open Access Publications

Rotavirus (RV)-encoded nonstructural protein 1 (NSP1), the product of gene segment 5, effectively antagonizes host interferon (IFN) signaling via multiple mechanisms. Recent studies with the newly established RV reverse genetics system indicate that NSP1 is not essential for the replication of the simian RV SA11 strain in cell culture. However, the role of NSP1 in RV infection

Myeloid-Derived Suppressor Cells Mediate T Cell Dysfunction In Nonhuman Primate Tb Granulomas, Bindu Singh, Dhiraj K Singh, Shashank R Ganatra, Ruby A Escobedo, Shabaana Khader, Larry S Schlesinger, Deepak Kaushal, Smriti Mehra

Open Access Publications

Myeloid-derived suppressor cells (MDSCs) represent an innate immune cell population comprised of immature myeloid cells and myeloid progenitors with very potent immunosuppressive potential. MDSCs are reported to be abundant in the lungs of active tuberculosis (TB) patients. We sought to perform an in-depth study of MDSCs during latent TB infection (LTBI) and active TB (ATB) using the nonhuman primate (NHP) model of pulmonary TB. We found a higher proportion of granulocytic, polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in the lungs of ATB animals compared to those with LTBI or naive control animals. Active disease in the lung, but not LTBI, was …

Ccr2 Signaling Restricts Sars-Cov-2 Infection, Abigail Vanderheiden, Jeronay Thomas, Allison L Soung, Meredith E Davis-Gardner, Katharine Floyd, Fengzhi Jin, David A Cowan, Kathryn Pellegrini, Pei-Yong Shi, Arash Grakoui, Robyn S Klein, Steven E Bosinger, Jacob E Kohlmeier, Vineet D Menachery, Mehul S Suthar

Open Access Publications

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a historic pandemic of respiratory disease (coronavirus disease 2019 [COVID-19]), and current evidence suggests that severe disease is associated with dysregulated immunity within the respiratory tract. However, the innate immune mechanisms that mediate protection during COVID-19 are not well defined. Here, we characterize a mouse model of SARS-CoV-2 infection and find that early CCR2 signaling restricts the viral burden in the lung. We find that a recently developed mouse-adapted SARS-CoV-2 (MA-SARS-CoV-2) strain as well as the emerging B.1.351 variant trigger an inflammatory response in the lung characterized by the expression of …

A Protocol For The Induction Of Experimental Necrotizing Enterocolitis In Neonatal Mice, Lila S Nolan, Qingqing Gong, Heather N Hofmeister, Misty Good

Open Access Publications

Recapitulating human NEC using animal models has been insightful in dissecting the signaling pathways, immune-mediated mechanisms, genetic signatures, and the intestinal architecture of NEC. This protocol describes an

Antibody-Drug Conjugates Plus Janus Kinase Inhibitors Enable Mhc-Mismatched Allogeneic Hematopoietic Stem Cell Transplantation, Stephen P Persaud, Julie K Ritchey, Sena Kim, Sora Lim, Peter G Ruminski, Matthew L Cooper, Michael P Rettig, Jaebok Choi, John F Dipersio

Open Access Publications

Despite the curative potential of hematopoietic stem cell transplantation (HSCT), conditioning-associated toxicities preclude broader clinical application. Antibody-drug conjugates (ADCs) provide an attractive approach to HSCT conditioning that minimizes toxicity while retaining efficacy. Initial studies of ADC conditioning have largely focused on syngeneic HSCT. However, to treat acute leukemias or induce tolerance for solid organ transplantation, this approach must be expanded to allogeneic HSCT (allo-HSCT). Using murine allo-HSCT models, we show that pharmacologic Janus kinase 1/2 (JAK1/2) inhibition combined with CD45- or cKit-targeted ADCs enables robust multilineage alloengraftment. Strikingly, myeloid lineage donor chimerism exceeding 99% was achievable in fully MHC-mismatched HSCT …

Multicenter Randomized Phase Ii Trial Of Atezolizumab With Or Without Cobimetinib In Biliary Tract Cancers, Mark Yarchoan, Andrea Wang-Gillam, Et Al

Open Access Publications

BACKGROUNDMEK inhibitors have limited activity in biliary tract cancers (BTCs) as monotherapy but are hypothesized to enhance responses to programmed death ligand 1 (PD-L1) inhibition.METHODSThis open-label phase II study randomized patients with BTC to atezolizumab (anti-PD-L1) as monotherapy or in combination with cobimetinib (MEK inhibitor). Eligible patients had unresectable BTC with 1 to 2 lines of prior therapy in the metastatic setting, measurable disease, and Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1. The primary endpoint was progression-free survival (PFS).RESULTSSeventy-seven patients were randomized and received study therapy. The trial met its primary endpoint, with a …

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 …

Activation Of The Α1Β2Γ2l Gaba Receptor By Physiological Agonists, Spencer R Pierce, Allison L Germann, Gustav Akk

Open Access Publications

The Cl

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

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 …

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, …

From Canines To Humans: Clinical Importance Of Staphylococcus Pseudintermedius, Karen C. Carroll, Carey-Ann D. Burnham, Lars F. Westblade

Open Access Publications

No abstract provided.

A Reevaluation Of The Tolerability And Effects Of Single-Dose Ivermectin Treatment On Onchocerca Volvulus Microfilariae In The Skin And Eyes In Eastern Ghana, Nicholas O Opoku, Michael E Gyasi, Felix Doe, Daphne Lew, Augustine R Hong, Sithembele Chithenga, Peter U Fischer, Christopher L King, Gary J Weil

Open Access Publications

Mass administration of ivermectin (IVM) has significantly reduced onchocerciasis prevalence, intensity, and morbidity in most endemic areas. Most IVM clinical trials were performed long ago in persons with high-intensity infections that are uncommon in West Africa today. This cohort treatment study recruited participants from a hypoendemic area in eastern Ghana to reevaluate the efficacy and tolerability of IVM with a special focus on the kinetics of microfilaria (Mf) clearance. Mf in the skin and anterior chambers (AC) were assessed by skin snip and slit lamp examinations at baseline and at 3 and 6 months after treatment with IVM 150 μg/kg. …

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 …

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

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.

Ero1-Pdi Redox Signaling In Health And Disease, Vishwanath Jha, Tripti Kumari, Vijayprakash Manickam, Zahra Assar, Kirk L. Olsen, Jeong-Ki Min, Jaehyung Cho

Open Access Publications

No abstract provided.

Directed Flow Of Beta Band Communication During Reorienting Of Attention Within The Dorsal Attention Network, Sara Spadone, Miroslaw Wyczesany, Stefania Della Penna, Maurizio Corbetta, Paolo Capotosto

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

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.

A Class Ii Mhc-Targeted Vaccine Elicits Immunity Against Sars-Cov-2 And Its Variants, Novalia Pishesha, Paul W Rothlauf, Mariel J Liebeskind, Maria A Vakaki, Louis-Marie Bloyet, Marjorie Cornejo Pontelli, Ma Xenia G Ilagan, William J Buchser, Sean P J Whelan, Et Al

Open Access Publications

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in over 100 million infections and millions of deaths. Effective vaccines remain the best hope of curtailing SARS-CoV-2 transmission, morbidity, and mortality. The vaccines in current use require cold storage and sophisticated manufacturing capacity, which complicates their distribution, especially in less developed countries. We report the development of a candidate SARS-CoV-2 vaccine that is purely protein based and directly targets antigen-presenting cells. It consists of the SARS-CoV-2 Spike receptor-binding domain (Spike

Cd36 Maintains The Gastric Mucosa And Associates With Gastric Disease, Miriam Jacome-Sosa, Zhi-Feng Miao, Vivek S Peche, Edward F Morris, Ramkumar Narendran, Kathryn M Pietka, Dmitri Samovski, Hei-Yong G Lo, Terri Pietka, Latisha Love-Gregory, Nada A Abumrad, Et Al

Open Access Publications

The gastric epithelium is often exposed to injurious elements and failure of appropriate healing predisposes to ulcers, hemorrhage, and ultimately cancer. We examined the gastric function of CD36, a protein linked to disease and homeostasis. We used the tamoxifen model of gastric injury in mice null for Cd36 (Cd36

Cytokine Exposure Mediates Transcriptional Activation Of The Orphan Nuclear Receptor Nur77 In Hematopoietic Cells, Orsola Di Martino, Haixia Niu, Gayla Hadwiger, Margaret A Ferris, John S Welch

Open Access Publications

The orphan nuclear receptor Nur77 is an immediate-early response gene that based on tissue and cell context is implicated in a plethora of cellular processes, including proliferation, differentiation, apoptosis, metabolism, and inflammation. Nur77 has a ligand-binding pocket that is obstructed by hydrophobic side groups. Naturally occurring, cell-endogenous ligands have not been identified, and Nur77 transcriptional activity is thought to be regulated through posttranslational modification and modulation of protein levels. To determine whether Nur77 is transcriptionally active in hematopoietic cells in vivo, we used an upstream activating sequence (UAS)-GFP transgenic reporter. We found that Nur77 is transcriptionally inactive in vivo in …