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Orthobunyaviruses: recent genetic and structural insights
Key Points
Orthobunyaviruses are arthropod-transmitted viruses that are characterized by a tripartite, negative-sense RNA genome. Some viruses in this family are associated with diseases in humans (such as fever and encephalitis) and domesticated animals (including abortion and teratogenic effects in offspring). Schmallenberg virus, which is a recently emerged member of the family, caused a disease outbreak in domesticated animals in Europe in 2012–2013.
Viral replication occurs in the cytoplasm of infected cells and viruses mature by budding in the Golgi complex. Although infection of mammalian cells usually results in cell death, replication in arthropod vector cells is not cytopathic and these cells become persistently infected.
Viral mRNA synthesis is primed by capped oligonucleotides that are derived from host cell mRNAs in a process that is known as cap snatching. The endonuclease activity that is responsible for generating the primers is contained in the amino-terminal domain of the viral RNA-dependent RNA polymerase protein.
The three-dimensional structure of the viral N (nucleocapsid) protein shows that it forms a tetramer that contains a novel fold with a central, positively charged groove that binds to the viral RNA.
The viral non-structural protein NSs is the major virulence factor and antagonizes the host innate immune response by causing global inhibition of RNA polymerase II-mediated transcription.
Possession of a segmented genome enables orthobunyaviruses to evolve rapidly by segment reassortment during mixed infections. Reassortment occurs widely in nature and reassortant viruses can have dramatically altered properties, such as increased virulence.
Little is known about the burden of orthobunyavirus disease and there is a need for improved global surveillance to monitor orthobunyavirus activity.
Orthobunyaviruses are transmitted by arthropod vectors and can infect humans, animals and crops. In this Review, Elliott describes recent genetic and structural advances that have revealed important insights into the composition of orthobunyavirus virions, viral transcription and replication, and viral interactions with the host innate immune response.
Orthobunyaviruses, which have small, tripartite, negative-sense RNA genomes and structurally simple virions composed of just four proteins, can have devastating effects on human health and well-being, either by causing disease in humans or by causing disease in livestock and crops. In this Review, I describe the recent genetic and structural advances that have revealed important insights into the composition of orthobunyavirus virions, viral transcription and replication and viral interactions with the host innate immune response. Lastly, I highlight outstanding questions and areas of future research.
Journal Article
Discovery of senolytics using machine learning
Cellular senescence is a stress response involved in ageing and diverse disease processes including cancer, type-2 diabetes, osteoarthritis and viral infection. Despite growing interest in targeted elimination of senescent cells, only few senolytics are known due to the lack of well-characterised molecular targets. Here, we report the discovery of three senolytics using cost-effective machine learning algorithms trained solely on published data. We computationally screened various chemical libraries and validated the senolytic action of ginkgetin, periplocin and oleandrin in human cell lines under various modalities of senescence. The compounds have potency comparable to known senolytics, and we show that oleandrin has improved potency over its target as compared to best-in-class alternatives. Our approach led to several hundred-fold reduction in drug screening costs and demonstrates that artificial intelligence can take maximum advantage of small and heterogeneous drug screening data, paving the way for new open science approaches to early-stage drug discovery.
Cellular senescence is involved in many disease processes but few senolytic compounds are currently known. Here, the authors report the discovery of three senolytics using machine learning models trained solely on published data, with large reductions in drug screening costs.
Journal Article
The Rolling Stones : all the songs : the story behind every track
A visual, song-by-song history of The Rolling Stones covers their studio albums, compilation albums, and more than one hundred singles, providing photographs, musician lists, and recording and song development information.
Book
A cautionary note on the use of N-acetylcysteine as a reactive oxygen species antagonist to assess copper mediated cell death
A new form of cell death has recently been proposed involving copper-induced cell death, termed cuproptosis. This new form of cell death has been widely studied in relation to a novel class of copper ionophores, including elesclomol and disulfiram. However, the exact mechanism leading to cell death remains contentious. The oldest and most widely accepted biological mechanism is that the accumulated intracellular copper leads to excessive build-up of reactive oxygen species and that this is what ultimately leads to cell death. Most of this evidence is largely based on studies using N-acetylcysteine (NAC), an antioxidant, to relieve the oxidative stress and prevent cell death. However, here we have demonstrated using inductively coupled mass-spectrometry, that NAC pretreatment significantly reduces intracellular copper uptake triggered by the ionophores, elesclomol and disulfiram, suggesting that reduction in copper uptake, rather than the antioxidant activity of NAC, is responsible for the diminished cell death. We present further data showing that key mediators of reactive oxygen species are not upregulated in response to elesclomol treatment, and further that sensitivity of cancer cell lines to reactive oxygen species does not correlate with sensitivity to these copper ionophores. Our findings are in line with several recent studies proposing the mechanism of cuproptosis is instead via copper mediated aggregation of proteins, resulting in proteotoxic stress leading to cell death. Overall, it is vital to disseminate this key piece of information regarding NAC’s activity on copper uptake since new research attributing the effect of NAC on copper ionophore activity to quenching of reactive oxygen species is being published regularly and our studies suggest their conclusions may be misleading.
Journal Article
Pink Floyd : all the songs : the story behind every track
\"The newest addition to the best-selling All the Songs series details the unique recording history of Pink Floyd, one of the world's most commercially successful and influential rock bands. Since 1965, Pink Floyd haven been recording sonically experimental and philosophical music, selling more than 250 million records worldwide, including two of the best-selling albums of all time: The Dark Side of the Moon and The Wall. While much is known about this iconic group, few books provide a comprehensive history of their time in the studio. In Pink Floyd All the Songs, authors Margotin and Guesdon describe the origin of their nearly 200 released songs, details from the recording studio, what instruments were used, and behind-the-scenes stories of the tensions that helped drive the band. Organized chronologically by album, this massive, 544-page hardcover begins with their 1967 debut album The Piper at the Gates of Dawn, the only one recorded under founding member Syd Barrett's leadership; through the loss of Barrett and the addition of David Gilmour; to Richard Wright leaving the band in 1979 but returning; to Roger Waters leaving in 1985 and the albums recorded since his departure, including their 2014 farewell album, The Endless River, which was downloaded 12 million times on Spotify the week it was released. Packed with more than 500 photos, All the Songs is also filled with stories fans treasure, such as Waters working with engineer Alan Parsons to employ revolutionary recording techniques for The Dark Side of the Moon at Abbey Road Studios in 1972, or producer Bob's Ezrin's contribution in refining Water's original sprawling vision for The Wall.\"--Publisher's description.
BOOK
Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity
The specificity of interferon effectors across an expanded range of viruses is studied, with results indicating that positive-sense single-stranded RNA viruses are more susceptible to interferon-stimulated gene activity than negative-sense RNA or DNA viruses; in addition, the DNA sensor cGAS is shown to have an unappreciated role in RNA virus inhibition.
cGAS crucial to innate immunity
This study reports the use of cell culture models to scan an extensive interferon-stimulated gene (ISG) library for activity against a broad spectrum of viruses. The scan reveals that positive-sense single-stranded (ss)RNA viruses are more susceptible to ISG activities than negative-sense ssRNA viruses or a DNA virus. The DNA sensor cyclic GMP-AMP synthase (cGAS) is shown to inhibit several RNA viruses. The authors also generated
cGAS
knockout mice and showed an
in vivo
requirement for cGAS in antiviral responses.
The type I interferon (IFN) response protects cells from viral infection by inducing hundreds of interferon-stimulated genes (ISGs), some of which encode direct antiviral effectors
1
,
2
,
3
. Recent screening studies have begun to catalogue ISGs with antiviral activity against several RNA and DNA viruses
4
,
5
,
6
,
7
,
8
,
9
,
10
,
11
,
12
,
13
. However, antiviral ISG specificity across multiple distinct classes of viruses remains largely unexplored. Here we used an ectopic expression assay to screen a library of more than 350 human ISGs for effects on 14 viruses representing 7 families and 11 genera. We show that 47 genes inhibit one or more viruses, and 25 genes enhance virus infectivity. Comparative analysis reveals that the screened ISGs target positive-sense single-stranded RNA viruses more effectively than negative-sense single-stranded RNA viruses. Gene clustering highlights the cytosolic DNA sensor cyclic GMP-AMP synthase (
cGAS
, also known as
MB21D1
) as a gene whose expression also broadly inhibits several RNA viruses.
In vitro
, lentiviral delivery of enzymatically active cGAS triggers a STING-dependent, IRF3-mediated antiviral program that functions independently of canonical IFN/STAT1 signalling.
In vivo
, genetic ablation of murine cGAS reveals its requirement in the antiviral response to two DNA viruses, and an unappreciated contribution to the innate control of an RNA virus. These studies uncover new paradigms for the preferential specificity of IFN-mediated antiviral pathways spanning several virus families.
Journal Article
The company you keep
Jim Grant is a public interest lawyer and single father raising his daughter in the tranquil suburbs of Albany, New York. Grant's world is turned upside down when a brash young reporter exposes his true identity as a former 1970s antiwar radical fugitive wanted for murder.
DVD
Drug Combinations Targeting FAK and MEK Overcomes Tumor Heterogeneity in Glioblastoma
Background/Objectives: Glioblastoma (GBM) is an aggressive brain tumor with limited treatment options and poor prognosis, largely owing to its heterogeneity and the involvement of multiple intracellular signaling pathways that contribute to drug resistance. While recent advancements in targeted drug combination therapies, such as dabrafenib and trametinib, show promise for certain GBM subgroups, identifying effective drug combinations across the broader GBM population remains a challenge. Integrin-mediated signaling, particularly through Focal Adhesion Kinase (FAK), plays a pivotal role in GBM pathogenesis and invasion, making it a potential therapeutic target and component of future drug combination strategies. Methods: In this study, we utilized a chemogenomic screening approach to identify synergistic drug combinations that target FAK in glioblastoma. We initially employed a CRISPR-engineered GBM model to assess the effects of FAK depletion and subsequently discovered that combining FAK inhibitors such as VS4718 with MEK inhibitors, particularly trametinib, demonstrated synergistic effects. This potent combination was validated using various 2D and 3D assays, including cell viability/apoptosis assessment, synergistic analysis, cellular imaging, and target engagement assays. This combination also effectively inhibited spheroid growth and invasion across a diverse panel of patient-derived GBM stem cells. Molecular mechanisms underlying these effects include suppression of multiple kinase signaling pathways and enhanced apoptosis, elucidated using Reverse-Phase Protein Array (RPPA) profiling and Western blot validation. Result: In vivo, combination therapy significantly reduced the tumor volume in orthotopic transplantation models. Conclusions: These findings suggest that the combination of FAK and MEK inhibitors represents a promising therapeutic strategy to overcome the challenges of GBM treatment.
Journal Article