Autoantibodies targeting type I interferons: Prevalence, mechanisms of induction, and association with viral disease susceptibility

The type I IFN (IFN-I) system is essential to limit severe viral disease in humans. Thus, IFN-I deficiencies are associated with serious life-threatening infections. Remarkably, some rare individuals with chronic autoimmune diseases develop neutralizing autoantibodies (autoAbs) against IFN-Is thereby compromising their own innate antiviral defenses. Furthermore, the prevalence of anti-IFN-I autoAbs in apparently healthy individuals increases with age, such that ∼4% of those over 70 years old are affected. Here, I review the literature on factors that may predispose individuals to develop anti-IFN-I autoAbs, such as reduced self-tolerance caused by defects in the genes AIRE, NFKB2, and FOXP3 (among others), or by generally impaired thymus function, including thymic involution in the elderly. In addition, I discuss the hypothesis that predisposed individuals develop anti-IFN-I autoAbs following "autoimmunization" with IFN-Is generated during some acute viral infections, systemic inflammatory events, or chronic IFN-I exposure. Finally, I highlight the enhanced susceptibility that individuals with anti-IFN-I autoAbs appear to have towards viral diseases such as severe COVID-19, influenza, or herpes (e.g., varicella-zoster virus, herpes simplex virus, cytomegalovirus), as well as adverse reactions to live-attenuated vaccines. Understanding the mechanisms underlying development and consequences of anti-IFN-I autoAbs will be key to implementing effective prophylactic and therapeutic measures

Antiviral immunity triggered by infection-induced host transposable elements

Host silencing of transposable elements (TEs) is critical to prevent genome damage and inappropriate inflammation. However, new evidence suggests that a virus-infected host may re-activate TEs and co-opt them for antiviral defense. RNA-Seq and specialized bioinformatics have revealed the diversity of virus infections that induce TEs. Furthermore, studies with influenza virus have uncovered how infection-triggered changes to the SUMOylation of TRIM28, an epigenetic co-repressor, lead to TE de-repression. Importantly, there is a growing appreciation of how de-repressed TEs stimulate antiviral gene expression, either via cis-acting enhancer functions or via their recognition as viral mimetics by innate immune nucleic acid sensors (e.g. RIG-I, mda-5 and cGAS). Understanding how viruses trigger, and counteract, TE-based antiviral immunity should provide insights into pathogenic mechanisms

Flow unit prediction with limited permeability data using artificial neural network analysis

The Appalachian Basin has numerous abandoned or marginally producing oilfields having significant recoverable oil remaining in place. Typically production records and reservoir data is not available. Presented is a new methodology, applicable to any field having limited records, designed for reservoir characterization via flow unit identification.;This methodology utilizes limited core permeability data from a few wells as a key to predicting flow units within a field when only log-based data is available. Primary software tools used include NeuroShell 2, an artificial neural network (ANN) program, and the Boast98 numerical simulator.;Various techniques for flow unit identification including graphic approaches using the permeability-porosity relationship within a given flow unit and ANN (Kohonen) analysis are utilized as a part of the methodology developed. The core data and flow units are utilized in neural network models designed to predict flow units and permeability field-wide using only electric well logs. Field wide prediction of flow units and permeability are products of the study.;The study field selected was the Jacksonburg-Stringtown field. The producing horizon is the Upper Devonian Gordon sandstone. Discovered in 1895, waterflood operations were commenced in 1981. The characterization study utilizes core data and electric logs (gamma ray-density) from six core wells for flow unit identification.;Two dual five spots were selected in the field for verification of this new methodology. Reservoir simulation analysis utilizing the predicted flow units and permeability was completed for comparison to actual production records. A close match was achieved. As another comparison step a single layer simulation model for the two patterns was generated. The single layer model included the same inputs as the flow unit model except for thickness and average permeability. The simulation model utilizing flow units was a far more accurate prediction method

Influence of heterocycle substitution in π-functional materials for organic photovoltaics

Heterocycle substitution can have a dramatic, and potentially unintended, impact the physical, optical, electrochemical, and photovoltaic properties of donor materials used in organic electronics. A change as small as a heteroatom substitution up or down a group can selectively tune energy levels by either stabilizing or destabilizing them, resulting in wider or narrower bandgaps. Along the same lines, a substitution with a heteroatom from a different group can completely reverse the role of a building block from being π-electron acceptor to a π-electron donor. Full heterocycle substitution can further be used to tune the absorption of materials, by playing on strength of aromaticity. This dissertation reports the synthesis and characterization of various π-conjugated systems, and examines the role heterocycle substitution plays on the optical, electrochemical, and photovoltaic properties of the materials

Forging a new consensus: NUMSA and ANC hegemony in flux in South Africa

This thesis examines the extent to which the ANC is hegemonic within South Africa, the degree to which this hegemonic project is neoliberal, and how resistance to this project is articulated within civil society. Drawing on the work of authors such as Patrick Bond, Ashwin Desai, and Sagie Narsiah this thesis applies a Gramscian theoretical framework to examine ways in which neoliberalism is manifested through ANC economic policies and the ANC’s bid for hegemony within South Africa. It also explores the role of unions and social movements as sites of counter-hegemonic resistance, with an emphasis on the activities of the National Union of Metalworkers of South Africa (NUMSA) after 2014. This study employs an interpretative methodological approach combining analyses of electoral data, newspapers and interview transcripts of ‘organic intellectuals’ to critique power and dominance in post-Apartheid South Africa. This is keenly informed by Gramscian understandings of hegemony and ‘common sense’ which emphasise the importance of ‘organic intellectuals’ in contesting and forming the structures of the historic bloc. This thesis finds that the hegemonic project centred on the ANC is limited or fractured, with the failure of the ANC’s broadly neoliberal economic policies fostering division within the Tripartite Alliance. Further, although neoliberalism has deeply penetrated ‘common sense’ understandings, growing criticism of the ANC has fundamentally undermined the state’s ability to mobilise consent and build consensus. However, this hegemonic project is highly elastic, with the ANC tempering its neoliberal policies with state interventions in the form of state housing, public-works programmes, and social grants. Thus, despite being perceived by ‘organic intellectuals’ as lacking hegemony, the ANC still has electoral hegemony and has succeeded thus far in preventing the emergence of an alternative hegemonic project. Further, NUMSA’s attempt to bring together unions, social movements and community organisations within a United Front are of limited significance in challenging the hegemony of the ANC neoliberal project

Arrighi on Sino-Sudanese relations : trade, investment and diplomacy in the twenty-first century

This research project will investigate the increasingly complex and dynamic relationship between China and Sudan from 1995 to the present within the context of Giovanni Arrighi’s understandings of World Systems Theory. In this project I will examine how the relationship between China and Sudan has manifested through trade, investment, and diplomacy since 1995. Further, this dissertation will situate Sino-Sudanese relations within the context of Giovanni Arrighi’s theories regarding the roles of China and Africa within the current world-system. As such, this study will ask how the relationship between China and Sudan reflects Arrighi’s arguments concerning coreperiphery relations, declining US hegemony, the economic rise of China and its potential hegemonic challenge. In addition, the scope of this dissertation will include an examination of Sudan’s economic and political landscape prior to and after 1995, along with an overview of Arrighi’s work concerning China, Africa and Sino-African relations. Thus, this project will examine how Sino-Sudanese relations with respect to trade, investment, and diplomacy in the twenty-first century, reflect Arrighi’s understanding of the current world-system

Avoiding culture shock with the SARS-CoV-2 spike protein

When culturing SARS-CoV-2 in the laboratory it is vital to avoid deletions in the gene for the spike protein that could affect the interpretation of experiments

Two components of maintaining developmental competence: microRNA-21 in the maturing oocyte and autophagy induction in the follicular stage ovary

This dissertation describes two processes that the oocyte and ovary potentially utilize to maintain reproductive competence: autophagy in response to heat stress and microRNA-21 function during meiotic maturation. Heat stress (HS) occurs when heat accumulation (from internal and external sources) exceeds heat dissipation. HS is associated with seasonal infertility and therefore is a production issue and profitability constraint in the swine industry. Autophagy is the process by which somatic cells recycle cellular components and it is activated by a variety of stressors. Therefore, characterizing autophagy in the ovary and oocyte is valuable because of the potential of autophagy to mitigate the detrimental effects of HS. Additionally, we also characterized the function of a specific microRNA (miRNA), mircroRNA-21 (MIR21), during oocyte maturation and the breakdown of the germinal vesicle (GVBD). The developmental competence of the oocyte is determined by molecular events that occur up to and during GVBD, though there is almost entirely no transcription occurring during GVBD. Thus, the maturing oocyte is reliant on post-transcriptional gene regulation (PTGR) and/or interactions with the surrounding cumulus cells to regulate the mRNA repertoire and proteome prior to fertilization. We hypothesized that miRNA is active within the oocyte and its biogenesis is dependent on GVBD. To characterize the effect of HS on autophagy induction in the ovary and oocyte, we utilized both an in vivo model as well as in vitro model. Twelve gilts were synchronized and subjected to cyclical HS (n = 6) or thermal neutral (TN; n = 6) conditions for five days during the follicular phase. The abundance of autophagy-related proteins in total ovarian protein was compared between gilts that had either experienced TN conditions for 5 days or HS conditions for 5 days. Ovarian tissue was fixed and sectioned to compare the localization of autophagy-related proteins in the ovary between gilts that had either experienced TN or HS conditions for 5 days. Based on the effects of HS on cell morphology within the follicle and changes in autophagy-related proteins, autophagy induction occurs in response to HS during the follicular phase. To further characterize the autophagy response directly in the pig oocyte, cumulus-oocyte-complexes were aspirated from 2-4 mm follicles and subjected to different temperature treatments during in vitro maturation (IVM). The oocytes experienced either TN conditions throughout the entire IVM, or HS during the first or second half of IVM. The abundance of autophagy-related proteins was compared between metaphase II (MII) arrested oocytes, and the cleavage of LC3 was compared at different time points during IVM. This data suggests autophagy as a potential mechanism activated that the oocyte could use during environmental stress to recycle damaged cellular components to maintain developmental competence. IVM was also utilized to characterize the function of a specific miRNA, mircroRNA-21 (MIR21), during oocyte maturation and GVBD. MiRNA, a class of functional small RNA, interact with the 3′ untranslated region (UTR) of target mRNA to affect their abundance and translational efficiency. Of particular importance is miRNA-21 due to its role in regulating programmed cell death 4 (PDCD4), and ultimately inhibiting apoptosis. To characterize the function of MIR21 in relation to GVBD, pig oocytes collected from aspirated 2-4 mm follicles experienced IVM at normal conditions or in the presence of a chemical inhibitor of GVBD, 3-isobutyl-1-methylxanthine (IBMX). Oocytes were collected at different time points of IVM with or without IBMX. The state of GVBD was compared to the abundance of mature MIR21, abundance of PDCD4, and activation of nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB). The cumulative results of this study suggest that MIR21 is activated and important during meiotic maturation of the oocyte, and that NF-κB is potentially driving MIR21 increase in the oocyte

The multifunctional NS1 protein of influenza A viruses

The non-structural (NS1) protein of influenza A viruses is a non-essential virulence factor that has multiple accessory functions during viral infection. In recent years, the major role ascribed to NS1 has been its inhibition of host immune responses, especially the limitation of both interferon (IFN) production and the antiviral effects of IFN-induced proteins, such as dsRNA-dependent protein kinase R (PKR) and 2'5'-oligoadenylate synthetase (OAS)/RNase L. However, it is clear that NS1 also acts directly to modulate other important aspects of the virus replication cycle, including viral RNA replication, viral protein synthesis, and general host-cell physiology. Here, we review the current literature on this remarkably multifunctional viral protein. In the first part of this article, we summarize the basic biochemistry of NS1, in particular its synthesis, structure, and intracellular localization. We then discuss the various roles NS1 has in regulating viral replication mechanisms, host innate/adaptive immune responses, and cellular signalling pathways. We focus on the NS1-RNA and NS1-protein interactions that are fundamental to these processes, and highlight apparent strain-specific ways in which different NS1 proteins may act. In this regard, the contributions of certain NS1 functions to the pathogenicity of human and animal influenza A viruses are also discussed. Finally, we outline practical applications that future studies on NS1 may lead to, including the rational design and manufacture of influenza vaccines, the development of novel antiviral drugs, and the use of oncolytic influenza A viruses as potential anti-cancer agents.Publisher PDFPeer reviewe

SARS-CoV-2 takes the bait: Exosomes as endogenous decoys

Writing in PLOS Biology, Ching and colleagues show that ACE2-decorated exosomes are deployed as natural inhibitory decoys against SARS-CoV-2. High decoy levels correlate with improved patient outcomes, suggesting they directly help COVID-19 recovery and supporting the concept of successful future decoy-based therapies