The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has devastated the global economy and claimed more than 1.7 million lives, presenting an urgent global health crisis. ...To identify host factors required for infection by SARS-CoV-2 and seasonal coronaviruses, we designed a focused high-coverage CRISPR-Cas9 library targeting 332 members of a recently published SARS-CoV-2 protein interactome. We leveraged the compact nature of this library to systematically screen SARS-CoV-2 at two physiologically relevant temperatures along with three related coronaviruses (human coronavirus 229E HCoV-229E, HCoV-NL63, and HCoV-OC43), allowing us to probe this interactome at a much higher resolution than genome-scale studies. This approach yielded several insights, including potential virus-specific differences in Rab GTPase requirements and glycosylphosphatidylinositol (GPI) anchor biosynthesis, as well as identification of multiple pan-coronavirus factors involved in cholesterol homeostasis. This coronavirus essentiality catalog could inform ongoing drug development efforts aimed at intercepting and treating coronavirus disease 2019 (COVID-19) and help prepare for future coronavirus outbreaks.
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•SARS-CoV-2 host protein interactome CRISPR screens for SARS-CoV-2 and three coronaviruses•Parallel CRISPR screens uncover unique and shared coronavirus host factors•Numbers of interacting host proteins and functional interactors are not proportional•Identified SARS-CoV-2 host factors are expressed in relevant cells in the human airway
Building upon a published SARS-CoV-2 protein interactome, Hoffmann et al. use a custom CRISPR library to determine which of these interacting host proteins are essential for infection by SARS-CoV-2 virus as well as three seasonal coronaviruses. These factors represent potential targets to combat COVID-19 and perhaps future coronavirus outbreaks.
Informed by ecological and intersectional perspectives, this study examined how Black Americans’ reflections on the historical context of slavery and experiences with discrimination shaped their ...understandings of and experiences within their own relationships. In-depth semi-structured interviews were conducted with 14 individuals in romantic relationships. Findings of the thematic analysis covered five themes: comparing social climates, assumptions about Black relationships, the discrimination triad, an opportunity to respond, and valuing and celebrating Black love. Contemporary experiences of discrimination were a filter that echoed the historical devaluing and mistreatment of Black individuals and their relationships. Partners’ interactions around discrimination were critical opportunities to offer support to their romantic partner.
Stem cells are highly resistant to viral infection compared to their differentiated progeny; however, the mechanism is mysterious. Here, we analyzed gene expression in mammalian stem cells and cells ...at various stages of differentiation. We find that, conserved across species, stem cells express a subset of genes previously classified as interferon (IFN) stimulated genes (ISGs) but that expression is intrinsic, as stem cells are refractory to interferon. This intrinsic ISG expression varies in a cell-type-specific manner, and many ISGs decrease upon differentiation, at which time cells become IFN responsive, allowing induction of a broad spectrum of ISGs by IFN signaling. Importantly, we show that intrinsically expressed ISGs protect stem cells against viral infection. We demonstrate the in vivo importance of intrinsic ISG expression for protecting stem cells and their differentiation potential during viral infection. These findings have intriguing implications for understanding stem cell biology and the evolution of pathogen resistance.
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•Pluri-/multipotent stem cells exhibit intrinsic expression of ISGs•Different stem cells express cell-type-specific groups of ISGs•Intrinsically expressed ISGs mediate antiviral resistance ex vivo and in vivo•Dynamic expression of ISGs is conserved across species
Intrinsic expression of interferon-stimulated genes makes stem cells resistant to infections, preserving their pool throughout the organism’s lifespan.
Abstract
In this paper, we model the chemical evolution of a 0.25 M⊙ protoplanetary disc surrounding a 1 M⊙ star that undergoes fragmentation due to self-gravity. We use smoothed particle ...hydrodynamics including a radiative transfer scheme, along with a time-dependent chemical evolution code to follow the composition of the disc and resulting fragments over approximately 4000 yr. Initially, four quasi-stable fragments are formed, of which two are eventually disrupted by tidal torques in the disc. From the results of our chemical modelling, we identify species that are abundant in the fragments (e.g. H2O, H2S, HNO, N2, NH3, OCS, SO), species that are abundant in the spiral shocks within the disc (e.g. CO, CH4, CN, CS, H2CO) and species that are abundant in the circumfragmentary material (e.g. HCO+). Our models suggest that in some fragments it is plausible for grains to sediment to the core before releasing their volatiles into the planetary envelope, leading to changes in, e.g., the C/O ratio of the gas and ice components. We would therefore predict that the atmospheric composition of planets generated by gravitational instability should not necessarily follow the bulk chemical composition of the local disc material.
microRNAs (miRNAs) act as sequence-specific guides for Argonaute (AGO) proteins, which mediate posttranscriptional silencing of target messenger RNAs. Despite their importance in many biological ...processes, rules governing AGO-miRNA targeting are only partially understood. Here we report a modified AGO HITS-CLIP strategy termed CLEAR (covalent ligation of endogenous Argonaute-bound RNAs)-CLIP, which enriches miRNAs ligated to their endogenous mRNA targets. CLEAR-CLIP mapped ∼130,000 endogenous miRNA-target interactions in mouse brain and ∼40,000 in human hepatoma cells. Motif and structural analysis define expanded pairing rules for over 200 mammalian miRNAs. Most interactions combine seed-based pairing with distinct, miRNA-specific patterns of auxiliary pairing. At some regulatory sites, this specificity confers distinct silencing functions to miRNA family members with shared seed sequences but divergent 3'-ends. This work provides a means for explicit biochemical identification of miRNA sites in vivo, leading to the discovery that miRNA 3'-end pairing is a general determinant of AGO binding specificity.
Environmental mercury and its toxic effects Rice, Kevin M; Walker, Jr, Ernest M; Wu, Miaozong ...
Journal of preventive medicine and public health,
03/2014, Letnik:
47, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Mercury exists naturally and as a man-made contaminant. The release of processed mercury can lead to a progressive increase in the amount of atmospheric mercury, which enters the ...atmospheric-soil-water distribution cycles where it can remain in circulation for years. Mercury poisoning is the result of exposure to mercury or mercury compounds resulting in various toxic effects depend on its chemical form and route of exposure. The major route of human exposure to methylmercury (MeHg) is largely through eating contaminated fish, seafood, and wildlife which have been exposed to mercury through ingestion of contaminated lower organisms. MeHg toxicity is associated with nervous system damage in adults and impaired neurological development in infants and children. Ingested mercury may undergo bioaccumulation leading to progressive increases in body burdens. This review addresses the systemic pathophysiology of individual organ systems associated with mercury poisoning. Mercury has profound cellular, cardiovascular, hematological, pulmonary, renal, immunological, neurological, endocrine, reproductive, and embryonic toxicological effects.
ATP controls the crowd Rice, Allyson M.; Rosen, Michael K.
Science (American Association for the Advancement of Science),
05/2017, Letnik:
356, Številka:
6339
Journal Article
Recenzirano
A major energy carrier of the cell also promotes protein solubility
Adenosine triphosphate (ATP) is the canonical energy carrier that powers cellular machines, drives metabolic reactions, and serves ...as a precursor to nucleic acids. On page 753 of this issue, Patel
et al.
(
1
) propose a previously unknown function for ATP in maintaining protein solubility and preventing macromolecular aggregation. They show that at physiologic concentrations (2 to 8 mM), the physical properties of ATP alone enable it to dissolve liquid-liquid phase-separated droplets and amyloid fibers. These findings suggest an additional way for cells to use ATP to maintain proteostasis in the crowded cytoplasm and also fine-tune the material properties of nonmembrane-bound organelles and the cell interior in general.
Abstract Hepatocellular carcinoma (HCC) is the third leading fatal cancer worldwide and its incidence continues to increase. Chronic viral hepatitis involving either hepatitis B virus (HBV) or ...hepatitis C virus (HCV) infection is the leading etiology for HCC, making HCC prevention a major goal of antiviral therapy. While recent clinical observations and translational research have enhanced our understanding of the molecular mechanisms driving the initiation and progression of HCC, much remains unknown. Current data indicates that HCC tumors are highly complex and heterogeneous resulting from the aberrant function of multiple molecular pathways. This complex biology is responsible, at least in part, for the absence of highly efficient target-directed therapies for this deadly cancer. Additionally, the direct or indirect effect of HBV and HCV infection on the development of HCC is still a contentious issue. Thus, the question remains whether viral hepatitis-associated HCC stems from virus-specific factors, and/or from a general mechanism involving inflammation and tissue regeneration. In this review we summarize general mechanisms implicated in HCC, emphasizing data generated by new technologies available today. We also highlight specific pathways by which HBV and HCV could be involved in HCC pathogenesis. However, improvements to current in vitro and in vivo systems for both viruses will be needed to rigorously define the temporal sequence and specific pathway dysregulations that drive the strong clinical link between chronic hepatitis virus infection and HCC.
Aluminosilicate zeolites are traditionally used in high-temperature applications at low water vapour pressures where the zeolite framework is generally considered to be stable and static. ...Increasingly, zeolites are being considered for applications under milder aqueous conditions. However, it has not yet been established how neutral liquid water at mild conditions affects the stability of the zeolite framework. Here, we show that covalent bonds in the zeolite chabazite (CHA) are labile when in contact with neutral liquid water, which leads to partial but fully reversible hydrolysis without framework degradation. We present ab initio calculations that predict novel, energetically viable reaction mechanisms by which Al-O and Si-O bonds rapidly and reversibly break at 300 K. By means of solid-state NMR, we confirm this prediction, demonstrating that isotopic substitution of
O in the zeolitic framework occurs at room temperature in less than one hour of contact with enriched water.
Although a cure for HCV is on the near horizon, emerging drug cocktails will be expensive, associated with side-effects and resistance making a global vaccine an urgent priority given the estimated ...high incidence of infection around the world. Due to the highly heterogeneous nature of HCV, an effective HCV vaccine which could elicit broadly cross-neutralizing antibodies has represented a major challenge. In this study, we tested for the presence of cross-neutralizing antibodies in human volunteers who were immunized with recombinant glycoproteins gpE1/gpE2 derived from a single HCV strain (HCV1 of genotype 1a). Cross neutralization was tested in Huh-7.5 human hepatoma cell cultures using infectious recombinant HCV (HCVcc) expressing structural proteins of heterologous HCV strains from all known major genotypes, 1-7. Vaccination induced significant neutralizing antibodies against heterologous HCV genotype 1a virus which represents the most common genotype in North America. Of the 16 vaccinees tested, 3 were selected on the basis of strong 1a virus neutralization for testing of broad cross-neutralizing responses. At least 1 vaccinee was shown to elicit broad cross-neutralization against all HCV genotypes. Although observed in only a minority of vaccinees, our results prove the key concept that a vaccine derived from a single strain of HCV can elicit broad cross-neutralizing antibodies against all known major genotypes of HCV and provide considerable encouragement for the further development of a human vaccine against this common, global pathogen.
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