The rockefeller university

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.

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.

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.

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'.

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.

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.

Gag, the primary structural protein of HIV-1, is recruited to the plasma membrane for virus assembly by its matrix (MA) domain. Gag is subsequently cleaved into its component domains, causing structural maturation to repurpose the virion for cell entry. We determined the structure and arrangement of MA within immature and mature HIV-1 through cryo-electron tomography. We found that MA rearranges between two different hexameric lattices upon maturation. In mature HIV-1, a lipid extends out of the membrane to bind with a pocket in MA. Our data suggest that proteolytic maturation of HIV-1 not only assembles the viral capsid surrounding the genome but also repurposes the membrane-bound MA lattice for an entry or postentry function and results in the partial removal of up to 2500 lipids from the viral membrane.

Synopsis Terrestrial animals must often negotiate heterogeneous, varying environments. Accordingly, their locomotive strategies must adapt to a wide range of terrain, as well as to a range of speeds to accomplish different behavioral goals. Studies in Drosophila have found that inter-leg coordination patterns (ICPs) vary smoothly with walking speed, rather than switching between distinct gaits as in vertebrates (e.g., horses transitioning between trotting and galloping). Such a continuum of stepping patterns implies that separate neural controllers are not necessary for each observed ICP. Furthermore, the spectrum of Drosophila stepping patterns includes all canonical coordination patterns observed during forward walking in insects. This raises the exciting possibility that the controller in Drosophila is common to all insects, and perhaps more generally to panarthropod walkers. Here, we survey and collate data on leg kinematics and inter-leg coordination relationships during forward walking in a range of arthropod species, as well as include data from a recent behavioral investigation into the tardigrade Hypsibius exemplaris. Using this comparative dataset, we point to several functional and morphological features that are shared among panarthropods. The goal of the framework presented in this review is to emphasize the importance of comparative functional and morphological analyses in understanding the origins and diversification of walking in Panarthropoda.