The Impact Of Interferon Regulatory Factor 3 On The Immune Response To Herpes Simplex Virus Type I Infection

The type I interferon: IFN) cascade is critical in control of herpes simplex virus type I: HSV-1) infection and relies on specific recognition molecules to rapidly signal viral infection via interferon regulatory factor-3: IRF-3) -dependent pathways. The absence of these recognition molecules or the loss of IRF-3 would be predicted to render early recognition pathways inoperative and thus impact viral infection. However, previous results had produced contradictory results in terms of the role of IRF-3 during HSV-1 infection. In this study, infected IRF-3-/- immune cells were found to support increased HSV-1 replication compared to control cells. In addition, IRF-3 deficient cells exhibited delayed type I IFN synthesis following infection and were partially restored in the presence of exogenous IFN; blockade of the type I IFN receptor resulted in similar titers in control and IRF-3-/- cells. Together, the data demonstrated that defective and deficient type I IFN production in IRF-3-/- cells resulted in increased HSV-1 replication in vitro. In vivo, IRF-3 deficiency was found to have no significant impact on HSV-1 replication in peripheral tissues following ocular challenge with a laboratory: 17) or a neurovirulent strain: McKrae) of virus. However, IRF-3-/- mice were significantly more susceptible to central nervous system infection following both peripheral and intracranial infection with HSV-1. Increased viral replication and inflammatory cytokine production were observed in brain tissues of IRF-3-/- mice compared to control mice. In addition, the production of IFNβ and IFNα was delayed and reduced in IRF-3-/- brains. These data demonstrate a critical role for IRF-3 in control of central nervous system infection following HSV-1 challenge. Together, the data illustrate the importance of IRF-3 mediated pathways in initiating the type I IFN cascade necessary to control HSV-1 infection both in vitro and in vivo

Creating tissue on chip constructs in microtitre plates for drug discovery

We report upon a novel coplanar dielectrophoresis (DEP) based cell patterning system for generating transferrable hepatic cell constructs, resembling a liver-lobule, in culture. The use of paper reinforced gel substrates provided sufficient strength to enable these constructs to be transfered into 96-well plates for long term functional studies, including in the future, drug development studies. Experimental results showed that hepatic cells formed DEP field-induced structures corresponding to an array of lobule-mimetic patterns. Hepatic viability was observed over a period of 3 days by the use of a fluorescent cell staining technique, whilst the liver specific functionality of albumin secretion showed a significant enhancement due to the layer patterning of cell lines (HepG2/C3A), compared to 2D patterned cells and un-patterned control. This “build and transfer” concept could, in future, also be adapted for the layer-by-layer construction of organs-on-chip in microtitre formats

A New Future? The Catholic Church, Grassroots Justice, and Accountability

Between the 1970s and 1980s, Guatemalans, particularly the indigenous populations, were targets of a state-sponsored genocide. Several years after the genocide, Catholic Bishop Juan Gerardi of Guatemala City took the lead in creating the Recovery of Historical Memory Project which was an independent investigation into the events of the genocide. Gerardi was murdered before the report was made public. This paper will briefly discuss Gerardi’s work and his contribution to local justice in Guatemala. The author will then explore what contributions the Catholic Church could make in creating similar fact-finding missions. Could a grassroots mechanism such as the one Gerardi created be a more effective response in particular situations, given the political gridlock of local and national governments? This paper will explore this question and utilize an ongoing situation to examine whether it could be more effective than a government body

Treatment of Decompensated Alcoholic Liver Disease

Alcoholic liver disease (ALD) is a spectrum ranging from simple hepatic steatosis to alcoholic hepatitis and cirrhosis. Patients with severe alcoholic hepatitis can have clinical presentation almost similar to those with decompensated cirrhosis. Scoring with models like Maddrey discriminant function, a model for end-stage liver disease, Glasgow alcoholic hepatitis score, and Lille model are helpful in prognosticating patients with ALD. One of the first therapeutic goals in ALD is to induce alcohol withdrawal with psychotherapy or drugs. Most studies have shown that nutritional therapy improves liver function and histology in patients with ALD. The rationale for using glucocorticoids is to block cytotoxic and inflammatory pathways in patients with severe alcoholic hepatitis. Pentoxifylline, a tumor necrosis factor alpha (TNFα) suppressor, and infliximab, an anti-TNFα mouse/human chimeric antibody, has been extensively studied in patients with alcoholic hepatitis. Liver transplantation remains the definitive therapy for decompensated cirrhosis/alcoholic hepatitis despite the issues of recidivism, poor compliance with postoperative care, and being a self-inflicted disease

Return of the Coronavirus: 2019-nCoV

The emergence of a novel coronavirus (2019-nCoV) has awakened the echoes of SARSCoV from nearly two decades ago. Yet, with technological advances and important lessons gained from previous outbreaks, perhaps the world is better equipped to deal with the most recent emergent group 2B coronavirus

Creating tissue on chip constructs in microtitre plates for drug discovery

We report upon a novel coplanar dielectrophoresis (DEP) based cell patterning system for generating transferrable hepatic cell constructs, resembling a liver-lobule, in culture. The use of paper reinforced gel substrates provided sufficient strength to enable these constructs to be transfered into 96-well plates for long term functional studies, including in the future, drug development studies. Experimental results showed that hepatic cells formed DEP field-induced structures corresponding to an array of lobulemimetic patterns. Hepatic viability was observed over a period of 3 days by the use of a fluorescent cell staining technique, whilst the liver specific functionality of albumin secretion showed a significant enhancement due to the layer patterning of cell lines (HepG2/C3A), compared to 2D patterned cells and un-patterned control. This “build and transfer” concept could, in future, also be adapted for the layer-bylayer construction of organs-on-chip in microtitre formats

Dielectrophoresis: A Review of Applications for Stem Cell Research

Dielectrophoresis can discriminate distinct cellular identities in heterogeneous populations, and monitor cell state changes associated with activation and clonal expansion, apoptosis, and necrosis, without the need for biochemical labels. Demonstrated capabilities include the enrichment of haematopoetic stem cells from bone marrow and peripheral blood, and adult stem cells from adipose tissue. Recent research suggests that this technique can predict the ultimate fate of neural stem cells after differentiation before the appearance of specific cell-surface proteins. This review summarises the properties of cells that contribute to their dielectrophoretic behaviour, and their relevance to stem cell research and translational applications

Viral metagenomics, protein structure, and reverse genetics: Key strategies for investigating coronaviruses

Viral metagenomics, modeling of protein structure, and manipulation of viral genetics are key approaches that have laid the foundations of our understanding of coronavirus biology. In this review, we discuss the major advances each method has provided and discuss how future studies should leverage these strategies synergistically to answer novel questions

Bugs in the System

Immunity to respiratory virus infection is governed by complex biological networks that influence disease progression and pathogenesis. Systems biology provides an opportunity to explore and understand these multifaceted interactions based on integration and modeling of multiple biological parameters. In this review, we describe new and refined systems-based approaches used to model, identify, and validate novel targets within complex networks following influenza and coronavirus infection. In addition, we propose avenues for extension and expansion that can revolutionize our understanding of infectious disease processes. Together, we hope to provide a window into the unique and expansive opportunity presented by systems biology to understand complex disease processes within the context of infectious diseases

Coagulation and wound repair during COVID-19

While COVID-19 is best known as a respiratory infection, SARS-CoV-2 causes systemic disease manifestations including coagulopathies. Both dysregulated extracellular matrix remodeling pathways and circulating coagulation proteins are hallmarks of severe COVID-19 and often continue after the resolution of acute infection. Coagulation proteins have proven effective as biomarkers for severe disease and anti-coagulants are a mainstay of COVID-19 therapeutics in hospitalized patients. While much knowledge has been gained about the role of clotting pathway activation in COVID-19, much remains to be elucidated in this complex network of signaling pathways