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Found 37443 matches. Displaying 1041-1050
Poston D, Weisblum Y, Wise H, Templeton K, Jenks S, Hatziioannou T, Bieniasz P
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Absence of Severe Acute Respiratory Syndrome Coronavirus 2 Neutralizing Activity in Prepandemic Sera From Individuals With Recent Seasonal Coronavirus Infection (opens in new window)

CLINICAL INFECTIOUS DISEASES 2021 SEP 1; 73(5):E1208-E1211
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Cross-reactive immune responses elicited by seasonal coronaviruses might affect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) susceptibility and disease outcomes. We measured neutralizing activity against SARS-CoV-2 in prepandemic sera from patients with prior polymerase chain reaction scan-confirmed seasonal coronavirus infection. Although neutralizing activity against seasonal coronaviruses was detected in nearly all sera, cross-reactive neutralizing activity against SARS-CoV-2 was undetectable.
Nassir N, Tambi R, Bankapur A, Al Heialy S, Karuvantevida N, Khansaheb HH, Zehra B, Begum G, Hameid RA, Ahmed A, Deesi Z, Alkhajeh A, Uddin KMF, Akter H, Shabestari SAS, Almidani O, Islam A, Gaudet M, Kandasamy RK, Loney T, Abou Tayoun A, Nowotny N, Woodbury-Smith M, Rahman P, Kuebler WM, Hachim MY, Casanova JL, Berdiev BK, Alsheikh-Ali A, Uddin M
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Single-cell transcriptome identifies FCGR3B upregulated subtype of alveolar macrophages in patients with critical COVID-19 (opens in new window)

ISCIENCE 2021 SEP 24; 24(9):? Article 103030
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Understanding host cell heterogeneity is critical for unraveling disease mechanism. Utilizing large-scale single-cell transcriptomics, we analyzed multiple tissue specimens from patients with life-threatening COVID-19 pneumonia, compared with healthy controls. We identified a subtype of monocyte-derived alveolar macrophages (MoAMs) where genes associated with severe COVID-19 comorbidities are significantly upregulated in bronchoalveolar lavage fluid of critical cases. FCGR3B consistently demarcated MoAM subset in different samples fromsevere COVID-19 cohorts and in CCL3L1-upregulated cells from nasopharyngeal swabs. In silico findings were validated by upregulation of FCGR3B in nasopharyngeal swabs of severe ICU COVID-19 cases, particularly in older patients and those with comorbidities. Additional lines of evidence from transcriptomic data and in vivo of severe COVID- 19 cases suggest that FCGR3B may identify a specific subtype of MoAM in patients with severe COVID-19 that may present a novel biomarker for screening and prognosis, as well as a potential therapeutic target.
Solanich X, Rigo-Bonnin R, Gumucio VD, Bastard P, Rosain J, Philippot Q, Perez-Fernandez XL, Fuset-Cabanes MP, Gordillo-Benitez MA, Suarez-Cuartin G, Boza-Hernandez E, Riera-Mestre A, Parra-Martinez A, Colobran R, Antoli A, Navarro S, Rocamora-Blanch G, Framil M, Calatayud L, Corbella X, Casanova JL, Morandeira F, Sabater-Riera J
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Pre-existing Autoantibodies Neutralizing High Concentrations of Type I Interferons in Almost 10% of COVID-19 Patients Admitted to Intensive Care in Barcelona (opens in new window)

JOURNAL OF CLINICAL IMMUNOLOGY
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Background It is important to predict which patients infected by SARS-CoV-2 are at higher risk of life-threatening COVID-19. Several studies suggest that neutralizing auto-antibodies (auto-Abs) against type I interferons (IFNs) are predictive of critical COVID-19 pneumonia. Objectives We aimed to test for auto-Abs to type I IFN and describe the main characteristics of COVID-19 patients admitted to intensive care depending on whether or not these auto-Abs are present. Methods Retrospective analysis of all COVID-19 patients admitted to an intensive care unit (ICU) in whom samples were available, from March 2020 to March 2021, in Barcelona, Spain. Results A total of 275 (70.5%) out of 390 patients admitted to ICU were tested for type I IFNs auto-antibodies (alpha 2 and/or omega) by ELISA, being positive in 49 (17.8%) of them. Blocking activity of plasma diluted 1/10 for high concentrations (10 ng/mL) of IFNs was proven in 26 (9.5%) patients. Almost all the patients with neutralizing auto-Abs were men (92.3%). ICU patients with positive results for neutralizing IFNs auto-Abs did not show relevant differences in demographic, comorbidities, clinical features, and mortality, when compared with those with negative results. Nevertheless, some laboratory tests (leukocytosis, neutrophilia, thrombocytosis) related with COVID-19 severity, as well as acute kidney injury (17 [65.4%] vs. 100 [40.2%]; p = 0.013) were significantly higher in patients with auto-Abs. Conclusion Auto-Abs neutralizing high concentrations of type I IFNs were found in 9.5% of patients admitted to the ICU for COVID-19 pneumonia in a hospital in Barcelona. These auto-Abs should be tested early upon diagnosis of SARS-CoV-2 infection, as they account for a significant proportion of life-threatening cases.
Galea S, Vaughan R
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Taking an Anti-Health Inequity Approach to Counter the Unfair Burden of Poor Health (opens in new window)

AMERICAN JOURNAL OF PUBLIC HEALTH 2021 SEP; 111(9):1584-1585
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Malone B, Campbell EA
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Molnupiravir: coding for catastrophe (opens in new window)

NATURE STRUCTURAL & MOLECULAR BIOLOGY 2021 SEP; 28(9):706-708
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Molnupiravir, a wide-spectrum antiviral that is currently in phase 2/3 clinical trials for the treatment of COVID-19, is proposed to inhibit viral replication by a mechanism known as 'lethal mutagenesis'. Two recently published studies reveal the biochemical and structural bases of how molnupiravir disrupts the fidelity of SARS-CoV-2 genome replication and prevents viral propagation by fostering error accumulation in a process referred to as 'error catastrophe'.
Neehus AL, Moriya K, Nieto-Patlan A, Le Voyer T, Levy R, Ozen A, Karakoc-Aydiner E, Baris S, Yildiran A, Altundag E, Roynard M, Haake K, Migaud M, Dorgham K, Gorochov G, Abel L, Lachmann N, Dogu F, Haskologlu S, Ince E, El-Benna J, Uzel G, Kiykim A, Boztug K, Roderick MR, Shahrooei M, Brogan PA, Abolhassani H, Hancioglu G, Parvaneh N, Belot A, Ikinciogullari A, Casanova JL, Puel A, Bustamante J
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Impaired respiratory burst contributes to infections in PKC-deficient patients (opens in new window)

JOURNAL OF EXPERIMENTAL MEDICINE 2021 SEP 6; 218(9):? Article e20210501
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Patients with autosomal recessive protein kinase C delta (PKC delta) deficiency suffer from childhood-onset autoimmunity, including systemic lupus erythematosus. They also suffer from recurrent infections that overlap with those seen in patients with chronic granulomatous disease (CGD), a disease caused by defects of the phagocyte NADPH oxidase and a lack of reactive oxygen species (ROS) production. We studied an international cohort of 17 PKC delta-deficient patients and found that their EBV-B cells and monocyte-derived phagocytes produced only small amounts of ROS and did not phosphorylate p40(phox) normally after PMA or opsonized Staphylococcus aureus stimulation. Moreover, the patients' circulating phagocytes displayed abnormally low levels of ROS production and markedly reduced neutrophil extracellular trap formation, altogether suggesting a role for PKC delta in activation of the NADPH oxidase complex. Our findings thus show that patients with PKC delta deficiency have impaired NADPH oxidase activity in various myeloid subsets, which may contribute to their CGD-like infectious phenotype.
Hedrick SL, Luo D, Kaska S, Niloy KK, Jackson K, Sarma R, Horn J, Baynard C, Leggas M, Butelman ER, Kreek MJ, Prisinzano TE
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Design, synthesis, and preliminary evaluation of a potential synthetic opioid rescue agent (opens in new window)

JOURNAL OF BIOMEDICAL SCIENCE 2021 SEP 9; 28(1):? Article 62
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Background: One of the most prominent opioid analgesics in the United States is the high potency agonist fentanyl. It is used in the treatment of acute and chronic pain and as an anesthetic adjuvant. When used inappropriately, however, ingestion of just a few milligrams of fentanyl or other synthetic opioid can cause opioid-induced respiratory depression (OIRD), often leading to death. Currently, the treatment of choice for OIRD is the opioid receptor antagonist naloxone. Recent reports, however, suggest that higher doses or repeated dosing of naloxone (due to recurrence of respiratory depression) may be required to reverse fully fentanyl-induced respiratory depression, rendering this treatment inadequate. To combat this synthetic opioid overdose crisis, this research aims at identifying a novel opioid reversal agent with enhanced efficacy towards fentanyl and other synthetic opioids. Methods: A series of naltrexone analogues were characterized for their ability to antagonize the effects of fentanyl in vitro utilizing a modified forskolin-induced cAMP accumulation assay. Lead analogue 29 was chosen to undergo further PK studies, followed by in vivo pharmacological analysis to determine its ability to antagonize opioid-induced antinociception in the hot plate assay. Results: A series of potent MOR antagonists were identified, including the highly potent analogue 29 (IC50 =2.06 nM). Follow-up PK studies revealed 29 to possess near 100% bioavailability following IP administration. Brain concentrations of 29 surpassed plasma concentrations, with an apparent terminal half-life of similar to 80 min in mice. In the hot plate assay, 29 dose-dependently (0.01-0.1 mg/kg; IP) and fully antagonized the antinociception induced by oxycodone (5.6 mg/kg; IP). Furthermore, the dose of 29 that is fully effective in preventing oxycodone-induced antinociception (0.1 mg/kg) was ineffective against locomotor deficits caused by the KOR agonist U50,488. Conclusions: Methods have been developed that have utility to identify enhanced rescue agents for the treatment of OIRD. Analogue 29, possessing potent MOR antagonist activity in vitro and in vivo, provides a promising lead in our search for an enhanced synthetic opioid rescue agent.
Weis JS, Palmquist KH
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Reality Check: Experimental Studies on Microplastics Lack Realism (opens in new window)

APPLIED SCIENCES-BASEL 2021 SEP; 11(18):? Article 8529
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Environmental microplastics are gaining interest due to their ubiquity and the threat they pose to environmental and human health. Critical studies have revealed the abundance of microplastics in nature, while others have tested the impacts of these small plastics on organismal health in the laboratory. Yet, there is often a mismatch between these two areas of research, resulting in major discrepancies and an inability to interpret certain findings. Here, we focus on several main lines of inquiry. First, even though the majority of environmental microplastics are plastic microfibers from textiles, laboratory studies still largely use spherical microbeads. There are also inconsistencies between the measurements of microplastics in the environment as compared to the concentrations that tend to be used in experimental studies. Likewise, the period of exposure occurring in experimental studies and in the environment are vastly different. Lastly, although experimental studies often focus on a particular subset of toxic chemicals present on microplastics, textile microfibers carry other dyes and chemicals that are understudied. They also cause types of physical damage not associated with microspheres. This review will analyze the literature pertaining to these mismatches, focusing on aquatic organisms and model systems, and seek to inform a path forward for this burgeoning area of research.
Alciatore G, Ugelvig LV, Frank E, Bidaux J, Gal A, Schmitt T, Kronauer DJC, Ulrich Y
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Immune challenges increase network centrality in a queenless ant (opens in new window)

PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES 2021 SEP 8; 288(1958):? Article 20211456
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Social animals display a wide range of behavioural defences against infectious diseases, some of which increase social contacts with infectious individuals (e.g. mutual grooming), while others decrease them (e.g. social exclusion). These defences often rely on the detection of infectious individuals, but this can be achieved in several ways that are difficult to differentiate. Here, we combine non-pathogenic immune challenges with automated tracking in colonies of the clonal raider ant to ask whether ants can detect the immune status of their social partners and to quantify their behavioural responses to this perceived infection risk. We first show that a key behavioural response elicited by live pathogens (allogrooming) can be qualitatively recapitulated by immune challenges alone. Automated scoring of interactions between all colony members reveals that this behavioural response increases the network centrality of immune-challenged individuals through a general increase in physical contacts. These results show that ants can detect the immune status of their nest-mates and respond with a general 'caring' strategy, rather than avoidance, towards social partners that are perceived to be infectious. Finally, we find no evidence that changes in cuticular hydrocarbon profiles drive these behavioural effects.
Navrazhina K, Garcet S, Gonzalez J, Grand D, Frew JW, Krueger JG
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In-Depth Analysis of the Hidradenitis Suppurativa Serum Proteome Identifies Distinct Inflammatory Subtypes (opens in new window)

JOURNAL OF INVESTIGATIVE DERMATOLOGY 2021 SEP; 141(9):2197-2207
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Hidradenitis suppurativa is a chronic inflammatory dermatosis with presentations ranging from painful nodules and abscesses to draining tunnels. Using an unbiased proteomics approach, we assessed cardiovascular-, cardiometabolic-, and inflammation-related biomarkers in the serum of patients with moderate-to-severe hidradenitis suppurativa. The serum of patients with hidradenitis suppurativa clustered separately from that of healthy controls and had an upregulation of neutrophil-related markers (Cathepsin D, IL-17A, CXCL1). Patients with histologically diagnosed dermal tunnels had higher serum lipocalin-2 levels compared with those without tunnels. Consistent with this, patients with tunnels had a more neutrophilic-rich serum signature, marked by Cathepsin D, IL-17A, and IL-17D alterations. There was a significant serum.skin correlation between proteins in the serum and the corresponding mRNA expression in skin biopsies, with healthy-appearing perilesional skin demonstrating a significant correlation with neutrophil-related proteins in the serum. CSF3 mRNA levels in lesional skin significantly correlated with neutrophil-related proteins in the serum, suggesting that CFS3 in the skin may be a driver of neutrophilic inflammation. Clinical significantly correlated with the levels of lipocalin-2 and IL-17A in the serum. Using an unbiased, large-scale proteomic approach, we demonstrate that hidradenitis suppurativa is a systemic neutrophilic dermatosis, with a specific molecular signature associated with the presence of dermal tunnels.