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Found 37769 matches. Displaying 1181-1190
Schneider WM, Hoffmann HH
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Flavivirus-host interactions: an expanding network of and antiviral factors
CURRENT OPINION IN VIROLOGY 2022 FEB; 52(?):71-77
Flaviviruses are zoonotic pathogens transmitted by the bite of infected mosquitos and ticks and represent a constant burden to human health. Here we review recent literature aimed at uncovering how flaviviruses interact with the cells that they infect. A better understanding of these interactions may ultimately lead to novel therapeutic targets. We highlight several studies that employed low-biased methods to discover new protein-protein, protein-RNA, and genetic interactions, and spotlight recent work characterizing the host protein, TMEM41B, which has been shown to be critical for infection by diverse flaviviruses and coronaviruses.
Bader-Meunier B, Hadchouel A, Berteloot L, Polivka L, Beziat V, Casanova JL, Levy R
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Effectiveness and safety of ruxolitinib for the treatment of refractory systemic idiopathic juvenile arthritis like associated with interstitial lung disease : a case report
ANNALS OF THE RHEUMATIC DISEASES 2022 FEB; 81(2):? Article e20
Park J, Foox J, Hether T, Danko DC, Warren S, Kim Y, Reeves J, Butler DJ, Mozsary C, Rosiene J, Shaiber A, Afshin EE, MacKay M, Rendeiro AF, Bram Y, Chandar V, Geiger H, Craney A, Velu P, Melnick AM, Hajirasouliha I, Beheshti A, Taylor D, Saravia-Butler A, Singh U, Wurtele ES, Schisler J, Fennessey S, Corvelo A, Zody MC, Germer S, Salvatore S, Levy S, Wu SX, Tatonetti NP, Shapira S, Salvatore M, Westblade LF, Cushing M, Rennert H, Kriegel AJ, Elemento O, Imielinski M, Rice CM, Borczuk AC, Meydan C, Schwartz RE, Mason CE
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System-wide transcriptome damage and tissue identity loss in COVID-19 patients
CELL REPORTS MEDICINE 2022 FEB 15; 3(2):? Article 100522
The molecular mechanisms underlying the clinical manifestations of coronavirus disease 2019 (COVID-19), and what distinguishes them from common seasonal influenza virus and other lung injury states such as acute respiratory distress syndrome, remain poorly understood. To address these challenges, we combine transcriptional profiling of 646 clinical nasopharyngeal swabs and 39 patient autopsy tissues to define body wide transcriptome changes in response to COVID-19. We then match these data with spatial protein and expression profiling across 357 tissue sections from 16 representative patient lung samples and identify tissue-compartment-specific damage wrought by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, evident as a function of varying viral loads during the clinical course of infection and tissue-type-specific expression states. Overall, our findings reveal a systemic disruption of canonical cellular and transcriptional pathways across all tissues, which can inform subsequent studies to combat the mortality of COVID-19 and to better understand the molecular dynamics of lethal SARS-CoV-2 and other respiratory infections.
von Beeren C, Bruckner A, Hoenle PO, Ospina-Jara B, Kronauer DJC, Bluthgen N
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Multiple phenotypic traits as triggers of host attacks towards ant symbionts: body size, morphological gestalt, and chemical mimicry accuracy (vol 18, 46, 2021)
FRONTIERS IN ZOOLOGY 2022 JAN 11; 19(1):? Article 2
Merryman RW, Redd R, Jeter E, Wong JL, McHugh K, Reynolds C, Nazzaro M, Varden A, Brown JR, Crombie JL, Davids MS, Fisher DC, Jacobsen E, Jacobson CA, Kim AI, LaCasce AS, Ng SY, Odejide OO, Parry EM, Dahi PB, Nieto Y, Joyce RM, Chen YB, Herrera AF, Armand P, Ritz J
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Immune Reconstitution following High-Dose Chemotherapy and Autologous Stem Cell Transplantation with or without Pembrolizumab Maintenance Therapy in Patients with Lymphoma
TRANSPLANTATION AND CELLULAR THERAPY 2022 JAN; 28(1):?
Autologous stem cell transplantation (ASCT) is a standard of care for patients with chemosensitive, relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) and diffuse large B cell lymphoma (DLBCL). Whereas the clinical benefit of ASCT has traditionally been attributed solely to cytoreduction from intensive chemotherapy, ASCT has important immunogenic effects that may contribute to its antitumor efficacy and could provide a favorable immune environment for post-ASCT immune-based maintenance treatments. We previously reported clinical results of a phase II trial (ClinicalTrials.gov identifier NCT02362997) testing 8 doses of pembrolizumab maintenance therapy after ASCT for patients with R/R cHL or DLBCL. To clarify the impact of pembrolizumab on immune reconstitution, we compared the kinetics of peripheral blood immune cell recovery after ASCT for trial patients receiving pembrolizumab maintenance to those of a contemporaneous control cohort of similar patients undergoing ASCT without pembrolizumab maintenance. This study was conducted to characterize the impact of post-ASCT pembrolizumab maintenance therapy on immune reconstitution for patients with R/R DLBCL and cHL and to identify candidate biomarkers of efficacy and immune-related adverse events (irAEs). Peripheral blood (PB) mononuclear cell samples were prospectively collected at 1 to 18 months after ASCT and analyzed by flow cytometry using a panel of fluoro-phore-conjugated monoclonal antibodies to identify B cells, natural killer (NK) cells, and various dendritic cell (DC) and T cell subsets. A median of 5 (range, 1 to 8) post-ASCT PB samples were collected from 144 patients (59 in the pembrolizumab group and 85 in the control group). Clinical characteristics of the 2 cohorts were similar. Compared with cHL patients, DLBCL patients (all of whom received anti-CD20 monoclonal antibody therapy before ASCT) had delayed CD19 cell reconstitution that persisted for at least 18 months after ASCT. No other differences in immune reconstitution based on lymphoma subtype were observed. Post-ASCT pembrolizumab maintenance therapy was associated with an elevation in circulating DCs (driven by higher levels of plasmacytoid and immature DCs) that persisted for the duration of pembrolizumab treatment, along with a significant reduction in PD-1 T cells that persisted for 6 to 12 months after completion of pembrolizumab therapy. Despite the key role of T cells in mediating the effects of PD-1 blockade, pembrolizumab maintenance did not affect recovery of any T cell subsets. In an exploratory analysis, a higher baseline CD4 terminal effector memory cell count (defined as CD3CD4CD45RACD62L-) was associated with inferior progression-free survival (PFS), but only among patients who received pembrolizumab maintenance (P = .003). As continuous variables, lower absolute levels of NK cells (P = .009), PD-1 CD4 T cells (P = .005), and PD-1+ CD8+ T cells (P = .005) before pembrolizumab initiation were each associated with a higher risk of grade 2+ irAEs. Our findings indicate that post-ACST pembrolizumab maintenance therapy is associated with a persistent elevation of circulating DCs, but its impact on the reconstitution of other immune cells in peripheral blood appears limited. Our study suggests that early features of post-ASCT immune reconstitution could be associated with PFS and the risk of irAE and warrant additional investigation. (c) 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. (c) 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved. Superscript/Subscript Available
Marodi L
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COVID-19 in patients with primary immunodeficiency
ORVOSI HETILAP 2022 JAN; 163(5):166-170
The pandemic caused by the novel coronavirus (SARS-CoV-2) has resulted in tremendous challenges to the management of patients with primary immunodeficiencies (PIDs) representing a wide range of immunological and genetic entities. Preliminary data suggest that patients with PID would be at increased risk of severe disease and mortality from this newly emerged coronavirus. However, morbidity and mortality by SARS-CoV-2 may depend only partly on specific defect of immunity. Most of disease morbidity and mortality has been published to be related to previous damage of organs and tissues that had developed on the bases of PID before contracting SARS-CoV-2 or other, PID-independent disorders. In a small fraction of patients, impaired type I interferon immunity was found to predispose PID patients to severe coronavirus disease. In this review, we provide an update on published data about SARS-CoV-2 infections and COVID-19 in various PIDs.
Kieuvongngam V, Chen J
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Structures of the peptidase-containing ABC transporter PCAT1 under equilibrium and nonequilibrium conditions
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2022 JAN 25; 119(4):? Article e2120534119
ATP-binding cassette (ABC) transporters are ubiquitous molecular pumps that transport a broad range of substrates across biological membranes. Although the structure and function of ABC transporters has been studied extensively, our understanding of their energetics and dynamics remains limited. Here, we present studies of the peptidase-containing ABC transporter 1 (PCAT1), a polypeptide processing and secretion ABC transporter that functions via the classic alternating access mechanism. PCAT1 is a homodimer containing two peptidase (PEP) domains, two transmembrane domains, and two nucleotide-binding domains (NBDs). Using cryoelectron microscopy, we analyzed the structures of wild-type PCAT1 under conditions that either prevent or permit ATP hydrolysis and observed two completely different conformational distributions. In the presence of ATP but absence of Mg2+, PCAT1 adopts an NBD-dimerized, outward-facing conformation. The two PEP domains are dissociated from the transporter core, preventing uncoupled substrate cleavage. The addition of Mg2+ to promote ATP hydrolysis shifts the majority of the particles into NBDseparated, inward-facing conformations. Under this ATP turnover condition, only a small fraction of PCAT1 adopts the NBDdimerized conformation. These data give rise to two mechanistic conclusions: 1) the ATP-bound, NBD-dimerized conformation is the lowest energy state, and 2) the rate-limiting step in the PCAT1 transport cycle is the formation of the NBD dimer. The thermodynamic conclusion is likely a general property shared by many ABC transporters. The kinetic bottleneck, however, varies from transporter to transporter.
Abdelfattah AS, Ahuja S, Akkin T, Allu SR, Brake J, Boas DA, Buckley EM, Campbell RE, Chen AI, Cheng XJ, Cizmar T, Costantini I, De Vittorio M, Devor A, Doran PR, El Khatib M, Emiliani V, Fomin-Thunemann N, Fainman Y, Fernandez-Alfonso T, Ferri CGL, Gilad A, Han X, Harris A, Hillman EMC, Hochgeschwender U, Holt MG, Ji N, Kilic K, Lake EMR, Li L, Li TQ, Machler P, Miller EW, Mesquita RC, Nadella KMNS, Nagerl UV, Nasu Y, Nimmerjahn A, Ondrackova P, Pavone FS, Campos CP, Peterka DS, Pisano F, Pisanello F, Puppo F, Sabatini BL, Sadegh S, Sakadzic S, Shoham S, Shroff SN, Silver RA, Sims RR, Smith SL, Srinivasan VJ, Thunemann M, Tian L, Tian L, Troxler T, Valera A, Vaziri A, Vinogradov SA, Vitale F, Wang LV, Uhlirova H, Xu C, Yang CHE, Yang MH, Yellen G, Yizhar O, Zhao YX
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Neurophotonic tools for microscopic measurements and manipulation: status report
NEUROPHOTONICS 2022 JAN 1; 9(?):? Article 013001
Neurophotonics was launched in 2014 coinciding with the launch of the BRAIN Initiative focused on development of technologies for advancement of neuroscience. For the last seven years, Neurophotonics' agenda has been well aligned with this focus on neurotechnologies featuring new optical methods and tools applicable to brain studies. While the BRAIN Initiative 2.0 is pivoting towards applications of these novel tools in the quest to understand the brain, this status report reviews an extensive and diverse toolkit of novel methods to explore brain function that have emerged from the BRAIN Initiative and related large-scale efforts for measurement and manipulation of brain structure and function. Here, we focus on neurophotonic tools mostly applicable to animal studies. A companion report, scheduled to appear later this year, will cover diffuse optical imaging methods applicable to noninvasive human studies. For each domain, we outline the current state-of-the-art of the respective technologies, identify the areas where innovation is needed, and provide an outlook for the future directions. (C) The Authors. Published by SPIE under a Creative Commons Attribution 4.0 International License.
Akey CW, Singh D, Ouch C, Echeverria I, Nudelman I, Varberg JM, Yu ZL, Fang F, Shi Y, Wang JJ, Salzberg D, Song KK, Xu C, Gumbart JC, Suslov S, Unruh J, Jaspersen SL, Chait BT, Sali A, Fernandez-Martinez J, Ludtke SJ, Villa E, Rout MP
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Comprehensive structure and functional adaptations of the yeast nuclear pore complex
CELL 2022 JAN 20; 185(2):361-+
Nuclear pore complexes (NPCs) mediate the nucleocytoplasmic transport of macromolecules. Here we provide a structure of the isolated yeast NPC in which the inner ring is resolved by cryo-EM at sub-nanometer resolution to show how flexible connectors tie together different structural and functional layers. These connectors may be targets for phosphorylation and regulated disassembly in cells with an open mitosis. Moreover, some nucleoporin pairs and transport factors have similar interaction motifs, which suggests an evolutionary and mechanistic link between assembly and transport. We provide evidence for three major NPC variants that may foreshadow functional specializations at the nuclear periphery. Cryo-electron tomography extended these studies, providing a model of the in situ NPC with a radially expanded inner ring. Our comprehensive model reveals features of the nuclear basket and central transporter, suggests a role for the lumenal Pom152 ring in restricting dilation, and highlights structural plasticity that may be required for transport.
Sunkari YK, Siripuram VK, Nguyen TL, Flajolet M
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High-power screening (HPS) empowered by DNA-encoded libraries
TRENDS IN PHARMACOLOGICAL SCIENCES 2022 JAN; 43(1):4-15
The world is totally dependent on medications. As science progresses, new, better, and cheaper drugs are needed more than ever. The pharmaceutical industry has been predominantly dependent on high-throughput screening (HTS) for the past three decades. Considering that the discovery rate has been relatively constant, can one hope for a much-needed sudden trend uptick? DNA-encoded libraries (DELs) and similar technologies, that have several orders of magnitude more screening power than HTS, and that we propose to group together under the umbrella term of high-power screening (HPS), are very well positioned to do exactly that. HPS also offers novel screening options such as parallel screening, ex vivo and in vivo screening, as well as a new path to druggable alternatives such as proteolysis targeting chimeras (PROTACs). Altogether, HPS unlocks novel powerful drug discovery avenues.