Everywhere and all the time: accident, radical contingency, and Crash

What are the politics of the accident? This essay interrogates the accident trope’s dual meaning in critical theory and popular narrative as both historically endemic and conditional for a political theory of radical resistance and ethical relation. I explore this in Paul Haggis’ 2004 film Crash, a popular narrative that plots the accident to provide an opening for a politics of possibility and ethical engagement. However, this essay critiques efforts to situate accidents, and therefore contingency, as both historically endemic and politically resistant, arguing for the difficulty of reading a specific theory of political and ethical decision into something ontologically given. Crash stretches contingency to incorporate temporality itself, and in doing so nullifies consideration of institutional histories of race and class, which aesthetically foregrounds and troubles related assumptions made by a critical mode that too quickly reads a specific politics and ethics into contingency’s deviation from necessary law. The essay re-evaluates the accident’s political and ethical coordinates through reference to Ernesto Laclau and Chantal Mouffe’s theorisation of contingency as conditional for political meaning more generally. Accidents, it concludes, are politically and ethically mobile, if they, as Crash and theories of radical contingency contend, happen everywhere and all the time

The And of Modernism: On New Periodizations

The study of literary modernism is in the ascendant in the academy. From alternate modernisms, to neomodernisms, to metamodernism and global modernisms, modernism scholarship has evolved through a configuration of modernism into a cross-cultural and inter-generational aesthetic practice. This article critically examines the periodizing logic implicit in this new modernism scholarship, specifically as it pertains to the study of what is loosely called ‘neomodernism’, which we suggest presents a notable development in literary history for accounts of contemporary fiction and postmodern culture. We are principally interested in a recent trend we observe in modernism literary criticism concerning the futurization of the object (literary modernism), and of critical work thereupon. This work, which specifically addresses developments in contemporary Western Anglophone literature, seeks to extend the project of modernism (sometimes called its ‘promise’) into the present, understanding it as the principal agency in literary distinction and merit. We examine this criticism through a series of case studies, and discern three interconnecting strands in neomodernist criticism – three ways of futurizing modernism, and of self-futurizing modernism criticism

Metabibliographic Fiction: Metafiction After the Death of the Book in Steven Hall’s Maxwell’s Demon and Nicola Barker’s I Am Sovereign

This essay examines the combination of an aesthetic interest in the book with metafiction’s self-reflexive literary strategies in two recent British fictions, Steven Hall’s Maxwell’s Demon (2021) and Nicola Barker’s I Am Sovereign (2019). Both fictions, I argue, engage in what I describe as “metabibliographic fiction.” Metabibliographic fictions are fictions that explore the intellectual, narrative, and aesthetic dimensions of metafiction, but do so in ways that incorporate forms of self-reference into their linguistic and graphic structures that engage with the book as a media device. Situating this work within the context of what N. Katherine Hayles terms “postprint,” the essay places metabibliographic fiction at the critical intersection of textual materialism, studies of bookishness, and taxonomies of aesthetic self-consciousness. It then analyzes metafictional and metabibliographic devices in Maxwell’s Demon and I Am Sovereign in order to open theories of the contemporary book to metafiction’s narrative and intellectual legacies

How and Why is An Answer (Still) Correct? Maintaining Provenance in Dynamic Knowledge Graphs

Knowledge graphs (KGs) have increasingly become the backbone of many critical knowledge-centric applications. Most large-scale KGs used in practice are automatically constructed based on an ensemble of extraction techniques applied over diverse data sources. Therefore, it is important to establish the provenance of results for a query to determine how these were computed. Provenance is shown to be useful for assigning confidence scores to the results, for debugging the KG generation itself, and for providing answer explanations. In many such applications, certain queries are registered as standing queries since their answers are needed often. However, KGs keep continuously changing due to reasons such as changes in the source data, improvements to the extraction techniques, refinement/enrichment of information, and so on. This brings us to the issue of efficiently maintaining the provenance polynomials of complex graph pattern queries for dynamic and large KGs instead of having to recompute them from scratch each time the KG is updated. Addressing these issues, we present HUKA which uses provenance polynomials for tracking the derivation of query results over knowledge graphs by encoding the edges involved in generating the answer. More importantly, HUKA also maintains these provenance polynomials in the face of updates---insertions as well as deletions of facts---to the underlying KG. Experimental results over large real-world KGs such as YAGO and DBpedia with various benchmark SPARQL query workloads reveals that HUKA can be almost 50 times faster than existing systems for provenance computation on dynamic KGs

SARS-CoV-2 spike N-terminal domain modulates TMPRSS2-dependent viral entry and fusogenicity

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike N-terminal domain (NTD) remains poorly characterized despite enrichment of mutations in this region across variants of concern (VOCs). Here, we examine the contribution of the NTD to infection and cell-cell fusion by constructing chimeric spikes bearing B.1.617 lineage (Delta and Kappa variants) NTDs and generating spike pseudotyped lentivirus. We find that the Delta NTD on a Kappa or wild-type (WT) background increases S1/S2 cleavage efficiency and virus entry, specifically in lung cells and airway organoids, through use of TMPRSS2. Delta exhibits increased cell-cell fusogenicity that could be conferred to WT and Kappa spikes by Delta NTD transfer. However, chimeras of Omicron BA.1 and BA.2 spikes with a Delta NTD do not show more efficient TMPRSS2 use or fusogenicity. We conclude that the NTD allosterically modulates S1/S2 cleavage and spike-mediated functions in a spike context-dependent manner, and allosteric interactions may be lost when combining regions from more distantly related VOCs

Longitudinal analysis reveals that delayed bystander CD8+ T cell activation and early immune pathology distinguish severe COVID-19 from mild disease

The kinetics of the immune changes in COVID-19 across severity groups have not been rigorously assessed. Using immunophenotyping, RNA sequencing, and serum cytokine analysis, we analyzed serial samples from 207 SARS-CoV2-infected individuals with a range of disease severities over 12 weeks from symptom onset. An early robust bystander CD8+ T cell immune response, without systemic inflammation, characterized asymptomatic or mild disease. Hospitalized individuals had delayed bystander responses and systemic inflammation that was already evident near symptom onset, indicating that immunopathology may be inevitable in some individuals. Viral load did not correlate with this early pathological response but did correlate with subsequent disease severity. Immune recovery is complex, with profound persistent cellular abnormalities in severe disease correlating with altered inflammatory responses, with signatures associated with increased oxidative phosphorylation replacing those driven by cytokines tumor necrosis factor (TNF) and interleukin (IL)-6. These late immunometabolic and immune defects may have clinical implications

Age-related immune response heterogeneity to SARS-CoV-2 vaccine BNT162b2

Although two-dose mRNA vaccination provides excellent protection against SARS-CoV-2, there is little information about vaccine efficacy against variants of concern (VOC) in individuals above eighty years of age1. Here we analysed immune responses following vaccination with the BNT162b2 mRNA vaccine2 in elderly participants and younger healthcare workers. Serum neutralization and levels of binding IgG or IgA after the first vaccine dose were lower in older individuals, with a marked drop in participants over eighty years old. Sera from participants above eighty showed lower neutralization potency against the B.1.1.7 (Alpha), B.1.351 (Beta) and P.1. (Gamma) VOC than against the wild-type virus and were more likely to lack any neutralization against VOC following the first dose. However, following the second dose, neutralization against VOC was detectable regardless of age. The frequency of SARS-CoV-2 spike-specific memory B cells was higher in elderly responders (whose serum showed neutralization activity) than in non-responders after the first dose. Elderly participants showed a clear reduction in somatic hypermutation of class-switched cells. The production of interferon-γ and interleukin-2 by SARS-CoV-2 spike-specific T cells was lower in older participants, and both cytokines were secreted primarily by CD4 T cells. We conclude that the elderly are a high-risk population and that specific measures to boost vaccine responses in this population are warranted, particularly where variants of concern are circulating

Combined Point-of-Care Nucleic Acid and Antibody Testing for SARS-CoV-2 following Emergence of D614G Spike Variant

Rapid COVID-19 diagnosis in the hospital is essential, although this is complicated by 30%–50% of nose/throat swabs being negative by SARS-CoV-2 nucleic acid amplification testing (NAAT). Furthermore, the D614G spike mutant dominates the pandemic and it is unclear how serological tests designed to detect anti-spike antibodies perform against this variant. We assess the diagnostic accuracy of combined rapid antibody point of care (POC) and nucleic acid assays for suspected COVID-19 disease due to either wild-type or the D614G spike mutant SARS-CoV-2. The overall detection rate for COVID-19 is 79.2% (95% CI 57.8–92.9) by rapid NAAT alone. The combined point of care antibody test and rapid NAAT is not affected by D614G and results in very high sensitivity for COVID-19 diagnosis with very high specificity

SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion

The B.1.617.2 (Delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha)1. In vitro, B.1.617.2 is sixfold less sensitive to serum neutralizing antibodies from recovered individuals, and eightfold less sensitive to vaccine-elicited antibodies, compared with wild-type Wuhan-1 bearing D614G. Serum neutralizing titres against B.1.617.2 were lower in ChAdOx1 vaccinees than in BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies to the receptor-binding domain and the amino-terminal domain. B.1.617.2 demonstrated higher replication efficiency than B.1.1.7 in both airway organoid and human airway epithelial systems, associated with B.1.617.2 spike being in a predominantly cleaved state compared with B.1.1.7 spike. The B.1.617.2 spike protein was able to mediate highly efficient syncytium formation that was less sensitive to inhibition by neutralizing antibody, compared with that of wild-type spike. We also observed that B.1.617.2 had higher replication and spike-mediated entry than B.1.617.1, potentially explaining the B.1.617.2 dominance. In an analysis of more than 130 SARS-CoV-2-infected health care workers across three centres in India during a period of mixed lineage circulation, we observed reduced ChAdOx1 vaccine effectiveness against B.1.617.2 relative to non-B.1.617.2, with the caveat of possible residual confounding. Compromised vaccine efficacy against the highly fit and immune-evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era

Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity

The SARS-CoV-2 Omicron BA.1 variant emerged in 20211 and has multiple mutations in its spike protein2. Here we show that the spike protein of Omicron has a higher affinity for ACE2 compared with Delta, and a marked change in its antigenicity increases Omicron’s evasion of therapeutic monoclonal and vaccine-elicited polyclonal neutralizing antibodies after two doses. mRNA vaccination as a third vaccine dose rescues and broadens neutralization. Importantly, the antiviral drugs remdesivir and molnupiravir retain efficacy against Omicron BA.1. Replication was similar for Omicron and Delta virus isolates in human nasal epithelial cultures. However, in lung cells and gut cells, Omicron demonstrated lower replication. Omicron spike protein was less efficiently cleaved compared with Delta. The differences in replication were mapped to the entry efficiency of the virus on the basis of spike-pseudotyped virus assays. The defect in entry of Omicron pseudotyped virus to specific cell types effectively correlated with higher cellular RNA expression of TMPRSS2, and deletion of TMPRSS2 affected Delta entry to a greater extent than Omicron. Furthermore, drug inhibitors targeting specific entry pathways3 demonstrated that the Omicron spike inefficiently uses the cellular protease TMPRSS2, which promotes cell entry through plasma membrane fusion, with greater dependency on cell entry through the endocytic pathway. Consistent with suboptimal S1/S2 cleavage and inability to use TMPRSS2, syncytium formation by the Omicron spike was substantially impaired compared with the Delta spike. The less efficient spike cleavage of Omicron at S1/S2 is associated with a shift in cellular tropism away from TMPRSS2-expressing cells, with implications for altered pathogenesis