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

FOXO3 Expression and Function in the Pig Oocyte and Embryo

Forkhead box O3 (FOXO3), a member of the FOXO subfamily of Forkhead transcription factors, has been shown to play critical roles in apoptosis, oxidative stress, cell cycle and DNA repair. The objective of this study was to characterize FOXO3 expression and its function during oocyte maturation and early embryo development in the pig.We found: (1) FOXO3 is dynamically expressed at both mRNA and protein level in the maturing oocyte and early in vitro fertilized embryos. (2) FOXO3 protein is localized in the cytoplasm of pig maturing oocytes. (3) Co-culture with Doxorubicin (DOX, 2 µM) significantly altered the total FOXO3 protein level during in vitro maturation. (4) in vitromaturation with DOX (2µM) numerically increased maturation rate, but significantly decreased embryo development to the blastocyst stage after oocyte parthenogenetic activation. Our work provides useful data for functional study of FOXO3 protein in female gametogenesis and the potential impact on developing pig embryos, which could benefit animal reproductive health and provide foundational knowledge for improving swine reproductive efficiency

A transient homotypic interaction model for the influenza A virus NS1 protein effector domain

Influenza A virus NS1 protein is a multifunctional virulence factor consisting of an RNA binding domain (RBD), a short linker, an effector domain (ED), and a C-terminal 'tail'. Although poorly understood, NS1 multimerization may autoregulate its actions. While RBD dimerization seems functionally conserved, two possible apo ED dimers have been proposed (helix-helix and strand-strand). Here, we analyze all available RBD, ED, and full-length NS1 structures, including four novel crystal structures obtained using EDs from divergent human and avian viruses, as well as two forms of a monomeric ED mutant. The data reveal the helix-helix interface as the only strictly conserved ED homodimeric contact. Furthermore, a mutant NS1 unable to form the helix-helix dimer is compromised in its ability to bind dsRNA efficiently, implying that ED multimerization influences RBD activity. Our bioinformatical work also suggests that the helix-helix interface is variable and transient, thereby allowing two ED monomers to twist relative to one another and possibly separate. In this regard, we found a mAb that recognizes NS1 via a residue completely buried within the ED helix-helix interface, and which may help highlight potential different conformational populations of NS1 (putatively termed 'helix-closed' and 'helix-open') in virus-infected cells. 'Helix-closed' conformations appear to enhance dsRNA binding, and 'helix-open' conformations allow otherwise inaccessible interactions with host factors. Our data support a new model of NS1 regulation in which the RBD remains dimeric throughout infection, while the ED switches between several quaternary states in order to expand its functional space. Such a concept may be applicable to other small multifunctional proteins

Abnormal cognition, sleep, EEG and brain metabolism in a novel knock-in Alzheimer mouse, PLB1

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Animal-related factors associated with moderate-to-severe diarrhea in children younger than five years in western Kenya: A matched case-control study

Background Diarrheal disease remains among the leading causes of global mortality in children younger than 5 years. Exposure to domestic animals may be a risk factor for diarrheal disease. The objectives of this study were to identify animal-related exposures associated with cases of moderate-to-severe diarrhea (MSD) in children in rural western Kenya, and to identify the major zoonotic enteric pathogens present in domestic animals residing in the homesteads of case and control children. Methodology/Principal findings We characterized animal-related exposures in a subset of case and control children (n = 73 pairs matched on age, sex and location) with reported animal presence at home enrolled in the Global Enteric Multicenter Study in western Kenya, and analysed these for an association with MSD. We identified potentially zoonotic enteric pathogens in pooled fecal specimens collected from domestic animals resident at children’s homesteads. Variables that were associated with decreased risk of MSD were washing hands after animal contact (matched odds ratio [MOR] = 0.2; 95% CI 0.08–0.7), and presence of adult sheep that were not confined in a pen overnight (MOR = 0.1; 0.02–0.5). Variables that were associated with increased risk of MSD were increasing number of sheep owned (MOR = 1.2; 1.0–1.5), frequent observation of fresh rodent excreta (feces/urine) outside the house (MOR = 7.5; 1.5–37.2), and participation of the child in providing water to chickens (MOR = 3.8; 1.2–12.2). Of 691 pooled specimens collected from 2,174 domestic animals, 159 pools (23%) tested positive for one or more potentially zoonotic enteric pathogens (Campylobacter jejuni, C. coli, non-typhoidal Salmonella, diarrheagenic E. coli, Giardia, Cryptosporidium, or rotavirus). We did not find any association between the presence of particular pathogens in household animals, and MSD in children. Conclusions and significance Public health agencies should continue to promote frequent hand washing, including after animal contact, to reduce the risk of MSD. Future studies should address specific causal relations of MSD with sheep and chicken husbandry practices, and with the presence of rodents

Image-guided Placement of Magnetic Neuroparticles as a Potential High-Resolution Brain-Machine Interface

We are developing methods of noninvasively delivering magnetic neuroparticles™ via intranasal administration followed by image-guided magnetic propulsion to selected locations in the brain. Once placed, the particles can activate neurons via vibrational motion or magnetoelectric stimulation. Similar particles might be used to read out neuronal electrical pulses via spintronic or liquid-crystal magnetic interactions, for fast bidirectional brain-machine interface. We have shown that particles containing liquid crystals can be read out with magnetic resonance imaging (MRI) using embedded magnetic nanoparticles and that the signal is visible even for voltages comparable to physiological characteristics. Such particles can be moved within the brain (e.g., across midline) without causing changes to neurological firing

SN 2020jgb: A Peculiar Type Ia Supernova Triggered by a Massive Helium-Shell Detonation in a Star-Forming Galaxy

The detonation of a thin ($\lesssim$$0.03\,\mathrm{M_\odot}$) helium shell (He-shell) atop a $\sim$$1\,\mathrm{M_\odot}$ white dwarf (WD) is a promising mechanism to explain normal Type Ia supernovae (SNe Ia), while thicker He-shells and less massive WDs may explain some recently observed peculiar SNe Ia. We present observations of SN 2020jgb, a peculiar SN Ia discovered by the Zwicky Transient Facility (ZTF). Near maximum light, SN 2020jgb is slightly subluminous (ZTF $g$-band absolute magnitude $M_g$ between $-18.2$ and $-18.7$ mag depending on the amount of host galaxy extinction) and shows an unusually red color ($g_\mathrm{ZTF}-r_\mathrm{ZTF}$ between 0.4 and 0.2 mag) due to strong line-blanketing blueward of $\sim$5000 $\r{A}$. These properties resemble those of SN 2018byg, a peculiar SN Ia consistent with a thick He-shell double detonation (DDet) SN. Using detailed radiative transfer models, we show that the optical spectroscopic and photometric evolution of SN 2020jgb are broadly consistent with a $\sim$$0.95\,\mathrm{M_\odot}$ (C/O core + He-shell; up to $\sim$$1.00\,\mathrm{M_\odot}$ depending on the total host extinction) progenitor ignited by a thick ($\sim$$0.13\,\mathrm{M_\odot}$) He-shell. We detect a prominent absorption feature at $\sim$1 $\mu\mathrm{m}$ in the near-infrared (NIR) spectrum of SN 2020jgb, which could originate from unburnt helium in the outermost ejecta. While the sample size is limited, similar 1 $\mu\mathrm{m}$ features have been detected in all the thick He-shell DDet candidates with NIR spectra obtained to date. SN 2020jgb is also the first subluminous, thick He-shell DDet SN discovered in a star-forming galaxy, indisputably showing that He-shell DDet objects occur in both star-forming and passive galaxies, consistent with the normal SN Ia population.Comment: 23 pages, 10 figures. Updated to accepted version (ApJ