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Influenza A Virus (IAV) is a recurring respiratory virus with limited availability of antiviral therapies. Understanding host proteins essential for IAV infection can identify targets for alternative host-directed therapies (HDTs). Using affinity purification-mass spectrometry and global phosphoproteomic and protein abundance analyses using three IAV strains (pH1N1, H3N2, H5N1) in three human cell types (A549, NHBE, THP-1), we map 332 IAV-human protein-protein interactions and identify 13 IAV-modulated kinases. Whole exome sequencing of patients who experienced severe influenza reveals several genes, including scaffold protein AHNAK, with predicted loss-of-function variants that are also identified in our proteomic analyses. Of our identified host factors, 54 significantly alter IAV infection upon siRNA knockdown, and two factors, AHNAK and coatomer subunit COPB1, are also essential for productive infection by SARS-CoV-2. Finally, 16 compounds targeting our identified host factors suppress IAV replication, with two targeting CDK2 and FLT3 showing pan-antiviral activity across influenza and coronavirus families. This study provides a comprehensive network model of IAV infection in human cells, identifying functional host targets for pan-viral HDT.

The σ2 receptor has attracted intense interest in cancer imaging1, psychiatric disease2, neuropathic pain3-5 and other areas of biology6,7. Here we determined the crystal structure of this receptor in complex with the clinical candidate roluperidone2 and the tool compound PB288. These structures templated a large-scale docking screen of 490 million virtual molecules, of which 484 compounds were synthesized and tested. We identified 127 new chemotypes with affinities superior to 1 μM, 31 of which had affinities superior to 50 nM. The hit rate fell smoothly and monotonically with docking score. We optimized three hits for potency and selectivity, and achieved affinities that ranged from 3 to 48 nM, with up to 250-fold selectivity versus the σ1 receptor. Crystal structures of two ligands bound to the σ2 receptor confirmed the docked poses. To investigate the contribution of the σ2 receptor in pain, two potent σ2-selective ligands and one potent σ1/σ2 non-selective ligand were tested for efficacy in a mouse model of neuropathic pain. All three ligands showed time-dependent decreases in mechanical hypersensitivity in the spared nerve injury model9, suggesting that the σ2 receptor has a role in nociception. This study illustrates the opportunities for rapid discovery of in vivo probes through structure-based screens of ultra large libraries, enabling study of underexplored areas of biology.

To fight COVID-19, much effort has been directed toward in vitro drug repurposing. Here, we investigate the impact of colloidal aggregation, a common screening artifact, in these repurposing campaigns. We tested 56 drugs reported as active in biochemical assays for aggregation by dynamic light scattering and by detergent-based enzyme counter screening; 19 formed colloids at concentrations similar to their literature IC50's, and another 14 were problematic. From a common repurposing library, we further selected another 15 drugs that had physical properties resembling known aggregators, finding that six aggregated at micromolar concentrations. This study suggests not only that many of the drugs repurposed for SARS-CoV-2 in biochemical assays are artifacts but that, more generally, at screening-relevant concentrations, even drugs can act artifactually via colloidal aggregation. Rapid detection of these artifacts will allow the community to focus on those molecules that genuinely have potential for treating COVID-19.

Repurposing drugs as treatments for COVID-19, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has drawn much attention. Beginning with sigma receptor ligands and expanding to other drugs from screening in the field, we became concerned that phospholipidosis was a shared mechanism underlying the antiviral activity of many repurposed drugs. For all of the 23 cationic amphiphilic drugs we tested, including hydroxychloroquine, azithromycin, amiodarone, and four others already in clinical trials, phospholipidosis was monotonically correlated with antiviral efficacy. Conversely, drugs active against the same targets that did not induce phospholipidosis were not antiviral. Phospholipidosis depends on the physicochemical properties of drugs and does not reflect specific target-based activities-rather, it may be considered a toxic confound in early drug discovery. Early detection of phospholipidosis could eliminate these artifacts, enabling a focus on molecules with therapeutic potential.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a grave threat to public health and the global economy. SARS-CoV-2 is closely related to the more lethal but less transmissible coronaviruses SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV). Here, we have carried out comparative viral-human protein-protein interaction and viral protein localization analyses for all three viruses. Subsequent functional genetic screening identified host factors that functionally impinge on coronavirus proliferation, including Tom70, a mitochondrial chaperone protein that interacts with both SARS-CoV-1 and SARS-CoV-2 ORF9b, an interaction we structurally characterized using cryo-electron microscopy. Combining genetically validated host factors with both COVID-19 patient genetic data and medical billing records identified molecular mechanisms and potential drug treatments that merit further molecular and clinical study.

A newly described coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of coronavirus disease 2019 (COVID-19), has infected over 2.3 million people, led to the death of more than 160,000 individuals and caused worldwide social and economic disruption1,2. There are no antiviral drugs with proven clinical efficacy for the treatment of COVID-19, nor are there any vaccines that prevent infection with SARS-CoV-2, and efforts to develop drugs and vaccines are hampered by the limited knowledge of the molecular details of how SARS-CoV-2 infects cells. Here we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins that physically associated with each of the SARS-CoV-2 proteins using affinity-purification mass spectrometry, identifying 332 high-confidence protein-protein interactions between SARS-CoV-2 and human proteins. Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (of which, 29 drugs are approved by the US Food and Drug Administration, 12 are in clinical trials and 28 are preclinical compounds). We screened a subset of these in multiple viral assays and found two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the sigma-1 and sigma-2 receptors. Further studies of these host-factor-targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.

An outbreak of the novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 290,000 people since the end of 2019, killed over 12,000, and caused worldwide social and economic disruption1,2. There are currently no antiviral drugs with proven efficacy nor are there vaccines for its prevention. Unfortunately, the scientific community has little knowledge of the molecular details of SARS-CoV-2 infection. To illuminate this, we cloned, tagged and expressed 26 of the 29 viral proteins in human cells and identified the human proteins physically associated with each using affinity- purification mass spectrometry (AP-MS), which identified 332 high confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 existing FDA-approved drugs, drugs in clinical trials and/or preclinical compounds, that we are currently evaluating for efficacy in live SARS-CoV-2 infection assays. The identification of host dependency factors mediating virus infection may provide key insights into effective molecular targets for developing broadly acting antiviral therapeutics against SARS-CoV-2 and other deadly coronavirus strains.

Representing a shift in archival methods, oral history is increasingly used alongside more traditional methods of documentation to capture institutional and community histories. In this article, the authors demonstrate how the Student Help Lived Experience Project at the Queens College Library’s Special Collections and Archives (SCA) provided a vital supplement to more traditional methods of archival documentation. SCA was able to leverage resources provided by a partnering organization and a newly established graduate fellowship to bolster its relationship with other entities on campus and to engage alumni in a participatory, collaborative effort that centered their knowledge and interests. This article highlights models and lessons from the project and explores how oral histories collected for the project amplify existing collections in the archives. The authors found that revisiting collections through oral histories introduced nuance and complexity not available in the physical collections. The oral histories collected for the project enriched the historical narrative, bringing into vivid relief an important chapter in civil rights and Queens College history by uncovering personal motivations, details, and life lessons of interest to a wide audience of archives users. [ABSTRACT FROM AUTHOR]

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Queens Memory is a local community archiving project co-administered by the Queens Public Library and Queens College Library. During the COVID-19 pandemic, Queens Memory embarked on a collaborative series of online programs that covered social justice, current events, and the creation of social change. This programming built upon ongoing community oral history and documentation efforts. This article explores how the public programs and oral history initiatives fueled one another, serving to uplift diverse voices within our communities and preserve those voices in the archives. Key ingredients of the programs are discussed, including technology, outreach, collaboration, consent, and format. [ABSTRACT FROM AUTHOR]

Copyright of Revue Francaise d'Allergologie is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Résumé L’anaphylaxie alimentaire induite par l’effort (AAIE) peut être la cause d’une réaction anaphylactique sévère. Dans cette observation concernant un jeune homme de 26 ans, marin embarqué dans la marine nationale, la survenue d’un tel épisode anaphylactique peut mettre fin à une carrière à la mer. L’AAIE est connue depuis la fin des années 1970. Peu d’études sont disponibles concernant sa prévalence qui est probablement sous-estimée. De nombreux aliments peuvent être en cause. La gliadine du gluten contenue dans les farines des céréales et plus particulièrement l’oméga-gliadine est l’allergène le plus fréquemment retrouvé dans l’AAIE. Certaines activités physiques sont plus fréquemment associées à l’anaphylaxie ainsi que la prise de certains médicaments et la prise d’alcool. Le mécanisme n’est pas parfaitement connu et plusieurs hypothèses sont avancées impliquant la modification de l’osmolarité, du pH, de la perméabilité du tube digestif ou de l’activité de la transglutaminase. Le traitement, en dehors de l’urgence, repose sur la prévention de la réaction. L’éducation du patient et de son entourage est essentielle dans la stratégie de prévention comme dans la prise en charge de l’urgence. Du fait de l’absence de thérapeutique spécifique de l’AAIE et de la nécessité de mise en place des mesures préventives, la poursuite d’une carrière exigeante comme celle de marin dans la marine nationale n’est pas possible. Food-dependent exercise-induced anaphylaxis (FDEIA) can be responsible for a strong anaphylactic reaction. In the present case, which concerned a 26-year-old sailor in the French Navy, the occurrence of such anaphylactic manifestations can end his seaman's career. FDEIA has been a well-known clinical entity since the late 1970s. Few studies are available concerning its prevalence, which is probably underestimated. Many different types of food can be involved. Gliadin proteins, a component of gluten, are present in cereal flours; one of them, omega-gliadin, is the cereal allergen most frequently causing FDEIA. Certain types of physical activities as well as certain drugs and consumption of alcohol are often linked with these anaphylactic reactions. The mechanism of these reactions is not perfectly known; several hypotheses, including modification of osmolarity and pH, defects in intestinal permeability and transglutaminase activity, have been proposed. Their management, excluding emergency treatment, is based on prevention. Education of the patient and members of the family circle is essential in the prevention strategy as well as in dealing with management of emergencies. Because of the lack of specific therapy for the management of FDEIA and the necessity of preventive measures, pursuing a demanding career like that of a sailor in the French Navy is not possible. [ABSTRACT FROM AUTHOR]

Résumé Introduction L’exposition aux allergènes d’intérieur est impliquée dans les maladies allergiques respiratoires et contribue à la morbidité asthmatique. L’allergène Mus m1, l’allergène majeur de la souris, joue un rôle dans l’asthme. Aucune étude ne s’est intéressée à la prévalence de cet allergène dans les bâtiments publics français. Méthodes Quarante-six échantillons de poussière ont été prélevés en aspirant le sol de 5 bâtiments publics en région Provence-Alpes-Côte-d’Azur. Ils ont été répartis en deux sous-groupes (petites et grandes structures). La poussière échantillonnée a été analysée pour évaluer la concentration de 5 allergènes d’intérieurs, avec la technique Multiplex Array for Indoor Allergens™ (MARIA). Résultats Les allergènes Mus m1, Fel d1, Can f1, Bla g2, Rat n1 sont retrouvés dans 93 %, 87 %, 61 %, 35 % et 7 % des échantillons, avec une concentration médiane (extrêmes) à 19,6 ng/g (0,2–6454,2), 37,9 ng/g (2,4–841,2), 28,2 ng/g (2,4–484,8), 188 ng/g (20,8–527,8) et 3,8 ng/g (3,8–12,8), respectivement. Les allergènes sont corrélés positivement deux à deux, sauf Mus m1. Dans les petites et grandes structures, la concentration médiane de Mus m1 est à 0,5 ng/g et 31,8 ng/g, respectivement ( p < 0,0001). L’allergène Rat n1 est uniquement présent dans les grandes structures, avec une concentration médiane à 3,8 ng/g. La dératisation est plus réalisée dans les grandes structures ( p < 0,005). Les déjections de souris ne sont pas associées à la détection de l’allergène Mus m1. Conclusion La prévalence de Mus m1 est importante mais sa concentration est souvent négligeable. L’allergène Mus m1 ne semblerait donc pas être un facteur de risque majeur de morbidité asthmatique en région PACA. Background Indoor allergen exposure is implicated in allergic respiratory disease and contributes to asthma morbidity. Mouse allergen plays a role in allergic asthma morbidity. However, no study is available on the distribution of this allergen in French public buildings. Methods Forty-six dust samples, collected by vacuuming during 2 different seasons, on the floor of five French public buildings in PACA region. They were divided into two subgroups (small and big structures), allowed to analyze five indoor allergens, with Multiplex ARray for Indoor Allergens™. A visual inspection and a questionnaire about the building and rooms were performed. Results Mus m1, Fel d1, Can f1, Bla g2, Rat n1 were found in 93%, 87%, 61%, 35% and 7% of the dust samples with a median concentration (range) at 19.6 ng/g (0.2–6454.2), 37.9 ng/g (2.4–841.2), 28.2 ng/g (2.4–484.8), 188 ng/g (20.8–527.8) and 3.8 ng/g (3.8–12.8), respectively. All these allergens were positively correlated two by two, except for Mus m1. In the small and big structures, the median level of Mus m1 is 0.5 ng/g and 31.8 ng/g, respectively ( P < 0.0001). Rat n1 was only present in big structures, with a median level at 3.8 ng/g. Deratting was more often used in big structures ( P < 0.005). Mouse droppings were not associated with detection of Mus m1. Conclusion The prevalence of mouse allergen was substantial but their levels were most often very low. Mus m1 does not appear a major risk factor for asthma morbidity in PACA region. [ABSTRACT FROM AUTHOR]

Résumé Une rhinite pollinique peut être associée aux allergies alimentaires. Plusieurs réactions croisées ont déjà été décrites comme le syndrome pomme-bouleau ou le syndrome cyprès-pêche. Nous rapportons ici, l’association chez 3 patients d’une rhinite allergique aux cyprès et d’une allergie alimentaire aux agrumes. Rhinitis due to pollen can be associated with food allergies. Several such cross-reactions, such as the apple-birch syndrome and the cypress-peach syndrome, have already been described. Here, we report the association in three patients of allergic rhinitis due to cypress pollen and food allergy to citrus fruits. [ABSTRACT FROM AUTHOR]