nuc Incidence of Rash After Amoxicillin Treatment in Children With Infectious Mononucleosis By pediatrics.aappublications.org Published On :: 2013-04-15T00:06:42-07:00 Antibiotics-induced rash in Epstein-Barr virus acute infectious mononucleosis, especially the aminopenicillins-induced type, was first described during the 1960s, with a reported incidence of 80% to 100%. This phenomenon was not further investigated but is well-established in pediatric textbooks.The main observation of this study is that rash induced by amoxicillin in confirmed Epstein-Barr virus acute infectious mononucleosis was found at a rate of ~30%, which is much lower than previously reported. (Read the full article) Full Article
nuc After MONUC, Should MONUSCO Continue to Support Congolese Military Campaigns? By feedproxy.google.com Published On :: Sun, 18 Jul 2010 22:00:00 GMT For more than a year and a half, UN peacekeepers have continuously supported military operations conducted by the Congolese armed forces (FARDC) against the Rwandan rebels of the Democratic Forces for the Liberation of Rwanda (FDLR) in North and South Kivu. Full Article
nuc Razer Tomahawk Gaming PC First Look: Intel's NUC 9 Extreme Mini PC, in Luxury Digs By www.pcmag.com Published On :: The new NUC is taking all sorts of forms at CES 2020, but none is as slick or as snazzy as Razer's early stab at this power-packed mini-PC platform. Full Article
nuc Public Advocate Calls on White House to Deny Subsidies for Coal and Nuclear Plants By news.delaware.gov Published On :: Thu, 03 May 2018 20:29:35 +0000 Delaware’s Public Advocate today issued a letter to the White House asking the Trump administration to deny a request for emergency bailouts for aging coal and nuclear power plants owned by a large regional energy supplier. Full Article Department of State News energy efficiency PJM Public Advocate public utilities white house
nuc China should TRIPLE nuclear arsenal to deter ‘warmongering’ US, editor of state-run Global Times argues By www.rt.com Published On :: Fri, 08 May 2020 12:55:17 +0000 China should drastically increase its stockpile of nuclear warheads to dissuade the United States from pursuing its strategic ambitions abroad, the editor of the Global Times has urged. Read Full Article at RT.com Full Article
nuc There’s too much hype about Pakistan’s nuclear capability: Anil Kakodkar By www.financialexpress.com Published On :: 2020-01-05T01:46:00+05:30 Nuclear physicists Kakodkar and Gangotra believe India’s nuclear industry “lost time” due to liability regime that followed 2008 nuclear deal, say country should aim for 50% nuclear energy, and insist that the space programme is about “national pride”, not jingoism Full Article India
nuc Exodus from Kiev: aftermath of Chernobyl nuclear accident - archive, 5 May 1986 By www.theguardian.com Published On :: 2020-05-05T04:30:27Z 5 May 1986: Moscow has seen many Russians arriving by train from Kiev in the disaster area MoscowThe first real signs of alarm among the Soviet public began to emerge over the weekend as Russians arriving by train from Kiev in the Chernobyl disaster area, began saying frankly that they were worried by radiation.In the last two days large numbers of unescorted children have been arriving here from the city by train, to be met by relatives and grandparents. Related: From the archive, 30 April 1986: Russia admits blast as death fears rise Related: Revisiting Chernobyl: 'It is a huge cemetery of dreams' Continue reading... Full Article Chernobyl nuclear disaster Russia Nuclear power
nuc Indian Government Confirms Cyberattack On Nuclear Plant By packetstormsecurity.com Published On :: Tue, 05 Nov 2019 15:11:55 GMT Full Article headline government india cyberwar
nuc Intel Fixes Severe NUC Firmware, Web Console Vulnerabilities By packetstormsecurity.com Published On :: Wed, 12 Jun 2019 15:28:10 GMT Full Article headline flaw patch intel
nuc Intel Fixes High-Severity Flaws In NUC, Discontinues Buggy Compute Module By packetstormsecurity.com Published On :: Wed, 15 Apr 2020 18:06:59 GMT Full Article headline flaw patch intel
nuc North Korean Malware Found On Indian Nuclear Plant's Network By packetstormsecurity.com Published On :: Wed, 30 Oct 2019 15:36:43 GMT Full Article headline hacker government india cyberwar korea scada
nuc Clean Energy Laws Signed in New Jersey: Offshore Wind, Efficiency, Solar, Storage and Nuclear Benefit By feedproxy.google.com Published On :: 2018-05-23T19:47:56Z Clean energy advocates rejoiced as legislation was passed today in New Jersey that will support the development of a massive amount of renewable energy, specifically community solar, energy storage, offshore wind and energy efficiency. The bill also props up nuclear power in the state with the establishment of zero-emission certificates. Full Article Energy Efficiency News Storage Solar Offshore Community Solar
nuc What Does the Nuclear Power Phase-Out Mean for Energy Storage? By feedproxy.google.com Published On :: 2019-01-23T15:38:48Z The power industry is facing a nuclear power dilemma, according to a report published by The Union of Concerned Scientists. UCS assessed the economic viability and performance of nuclear power plants operating in the United States and concluded that the retirement of these plants will likely result in the adoption of coal and natural gas for baseload power generation, two energy sources that contribute to carbon dioxide emissions. Full Article Microgrids Microgrids Grid Scale Storage DER Energy Efficiency DER Opinion & Commentary Utility Integration
nuc Tidal Lagoon’s Next Plant May Produce Power on Par with Nuclear By feedproxy.google.com Published On :: 2015-03-20T17:32:00Z The U.K. company planning the world’s first tidal-lagoon power station said its next plant may generate electricity at almost half the price. Full Article
nuc Japan Anticipates Clean Energy Will Edge Out Nuclear Power By feedproxy.google.com Published On :: 2015-04-28T18:12:00Z Japan anticipates that by 2030 clean energy such as solar and hydro will generate slightly more of the nation’s electricity than nuclear power plants. Full Article Storage Energy Efficiency Wind Power Solar
nuc Why New Nuclear Technology Hurts the Case for Renewables By feedproxy.google.com Published On :: 2014-05-16T15:48:00Z Does nuclear energy deserve a seat at the table alongside renewable energy technologies in weaning us off of fossil fuels and transitioning into a cleaner energy world? A new report published yesterday suggests not only will newer small modular reactor (SMR) technology be at least as expensive as larger reactors, it won't fit the needs of a more flexible grid system, and its development will siphon away funding from the truly renewable energy options that need it. Full Article Energy Efficiency Hydropower Baseload Energy Efficiency Bioenergy Policy Wind Power Solar Geothermal
nuc Nuclear Giant Exelon Launches Front Group to Cover Its Assets, Undermine Renewable Energy? By feedproxy.google.com Published On :: 2014-06-03T14:50:00Z Nuclear power, which accounts for 19 percent of the nation's electricity generation, is facing some serious challenges. Not only did its hoped-for renaissance fizzle out, four reactors shut down last year, another is closing this fall, and the nuclear giant Exelon says it will announce plant closings by the end of this year if market conditions don't improve. Full Article Hydropower Baseload Storage Bioenergy Policy Wind Power Opinion & Commentary Solar Geothermal
nuc Listen Up: Electricity from Nuclear Too Cheap to Meter — Or Not By feedproxy.google.com Published On :: 2014-08-07T14:24:00Z It's the environmentalist's third rail question: "Should we promote nuclear power as an expedient way to reduce CO2 emissions?" On the one hand, nuclear power generates electricity with almost negligible CO2 emissions — potentially a good way for our society to reverse the current global warming trends. On the other hand, nuclear power is...well...nuclear. Problems related to waste disposal, proliferation and high costs have not been solved, and we still have the occasional disaster. Full Article Baseload Storage Grid Scale Rooftop Wind Power Opinion & Commentary Solar Geothermal
nuc Japan Anticipates Clean Energy Will Edge Out Nuclear Power By feedproxy.google.com Published On :: 2015-04-28T18:12:00Z Japan anticipates that by 2030 clean energy such as solar and hydro will generate slightly more of the nation’s electricity than nuclear power plants. Full Article Storage Energy Efficiency Wind Power Solar
nuc The Impact of AI on Nuclear Deterrence: China, Russia, and the United States By feedproxy.google.com Published On :: Sat, 11 Apr 2020 02:47:58 +0000 By Lora Saalman HONOLULU (14 April 2020)—Artificial intelligence (AI) is an increasingly important component of weapons systems, with both positive and negative implications for nuclear deterrence. Integration of AI into military platforms has the potential to allow weaker nuclear-armed states to reset the imbalance of power, but at the same time it exacerbates fears that stronger states may further solidify their dominance and engage in more provocative actions. This is a summary only. Click the title for the full article, or visit www.EastWestCenter.org/Research-Wire for more. Full Article
nuc No-Debt Fanuc At A Multi-Year Low And Will Rebound When Economy Rebounds By seekingalpha.com Published On :: Mon, 13 Apr 2020 13:17:24 -0400 Full Article FANUF FANUY Holmes Osborne
nuc Green Shoots At Fanuc, But Beware Of Lawn Mowers By seekingalpha.com Published On :: Wed, 29 Apr 2020 10:12:35 -0400 Full Article ABB TER YASKY KUKAY FANUY Stephen Simpson CFA
nuc Gov't Won't Seek to Move away from Nuclear Power Too Fast...It Will Take 60 Years to Phase out By english.hankyung.com Published On :: 2017-08-18 09:02 President Moon Jae-in said on August 17, "The denuclearization bid by the current government is not so radical. It will take more than 60 years for us to reach that goal." In an interview in celebration of the 100th day since taking power, President Moon said, "The design life of nuclear reactors that were launched recently or under construction is 60 years. We plan to close reactors one by one as soon as their design life expires." His remarks are in reponse to criticism that his government'... Full Article
nuc Moon-Putin Meeting...Differ in How to Respond to North's Nuclear By english.hankyung.com Published On :: 2017-09-07 08:08 Moon Jae-in South Korean President and Vladimir Putin Russian President met on September 6 in Far Eastern Federal University in Russia's Vladivostok to discuss issues including the current North Korea nuclear crisis and economic cooperation between Russia and South Korea for 2 hours and 40 minutes. The two leaders agreed that the North's nuclear tests are "unacceptable" but differed in how it must be handled including cutting crude oil supplies to North Korea. President Moon said, "When ... Full Article
nuc Finucane condemns threat against journalists By article.wn.com Published On :: Sat, 09 May 2020 13:59 GMT 9 May, 2020 - by John Finucane Sinn Féin MP John Finucane has condemned loyalist threats against journalists and said the PSNI must do all in its power to put the crime gangs responsible out of... Full Article
nuc Donald Trump urges nuclear talks with China in call with Russia’s Vladimir Putin By www.scmp.com Published On :: Fri, 08 May 2020 00:43:18 +0800 US President Donald Trump called on Thursday for involving China in new arms control talks with Russia, telling Russian leader Vladimir Putin that they need to avoid a “costly arms race,” the White House said.“President Trump reaffirmed that the United States is committed to effective arms control that includes not only Russia, but also China, and looks forward to future discussions to avoid a costly arms race,” a statement said.Trump and Putin spoke by phone, also discussing the coronavirus… Full Article
nuc China may have secretly conducted low-level nuclear test blasts By www.smh.com.au Published On :: Thu, 16 Apr 2020 15:22:01 GMT US concerns about Beijing's possible pact breaches have been prompted by activities at China's Lop Nur nuclear test site throughout 2019. Full Article
nuc China needs more nuclear warheads: report By feedproxy.google.com Published On :: Sat, 09 May 2020 06:00:00 +0500 BEIJING: China should expand its stock of nuclear warheads to 1,000 soon, Global Times editor-in-chief Hu Xijin said on Friday, even as US President Donald Trump repeats his call for China to join an... [[ This is a content summary only. Visit my website for full links, other content, and more! ]] Full Article
nuc China needs more nuclear warheads: report By feedproxy.google.com Published On :: Sat, 09 May 2020 06:00:00 +0500 BEIJING: China should expand its stock of nuclear warheads to 1,000 soon, Global Times editor-in-chief Hu Xijin said on Friday, even as US President Donald Trump repeats his call for China to join an arms control treaty, foreign media reported.The Global Times is published by the People’s... Full Article
nuc China needs more nuclear warheads: report By feedproxy.google.com Published On :: Sat, 09 May 2020 06:00:00 +0500 BEIJING: China should expand its stock of nuclear warheads to 1,000 soon, Global Times editor-in-chief Hu Xijin said on Friday, even as US President Donald Trump repeats his call for China to join an arms control treaty, foreign media reported.The Global Times is published by the People’s... Full Article
nuc It would take Iran more than 4 months to develop nuclear weapons By www.newscientist.com Published On :: Wed, 08 Jan 2020 14:00:00 +0000 The US assassination of Iranian general Qassem Soleimani has raised fears of nuclear conflict, but Iran has been on the road to building nuclear weapons for some time Full Article
nuc Falling rocks can explode so hard that only nuclear weapons beat them By www.newscientist.com Published On :: Tue, 09 Oct 2018 16:00:05 +0000 If big rocks fall far enough they can explode with more energy than any non-nuclear bomb – and the ensuing shockwave can snap large trees half a kilometre away Full Article
nuc A Japanese nuclear power plant created a habitat for tropical fish By www.newscientist.com Published On :: Wed, 06 May 2020 19:00:03 +0000 A small increase in water temperature near a Japanese nuclear power plant allowed tropical fish to colonise the area, suggesting global warming will drastically alter some marine ecosystems Full Article
nuc Viral DNA Binding Protein SUMOylation Promotes PML Nuclear Body Localization Next to Viral Replication Centers By mbio.asm.org Published On :: 2020-03-17T01:30:14-07:00 ABSTRACT Human adenoviruses (HAdVs) have developed mechanisms to manipulate cellular antiviral measures to ensure proper DNA replication, with detailed processes far from being understood. Host cells repress incoming viral genomes through a network of transcriptional regulators that normally control cellular homeostasis. The nuclear domains involved are promyelocytic leukemia protein nuclear bodies (PML-NBs), interferon-inducible, dot-like nuclear structures and hot spots of SUMO posttranslational modification (PTM). In HAdV-infected cells, such SUMO factories are found in close proximity to newly established viral replication centers (RCs) marked by the adenoviral DNA binding protein (DBP) E2A. Here, we show that E2A is a novel target of host SUMOylation, leading to PTMs supporting E2A function in promoting productive infection. Our data show that SUMOylated E2A interacts with PML. Decreasing SUMO-E2A protein levels by generating HAdV variants mutated in the three main SUMO conjugation motifs (SCMs) led to lower numbers of viral RCs and PML-NBs, and these two structures were no longer next to each other. Our data further indicate that SUMOylated E2A binds the host transcription factor Sp100A, promoting HAdV gene expression, and represents the molecular bridge between PML tracks and adjacent viral RCs. Consequently, E2A SCM mutations repressed late viral gene expression and progeny production. These data highlight a novel mechanism used by the virus to benefit from host antiviral responses by exploiting the cellular SUMO conjugation machinery. IMPORTANCE PML nuclear bodies (PML-NBs) are implicated in general antiviral defense based on recruiting host restriction factors; however, it is not understood so far why viruses would establish viral replication centers (RCs) juxtaposed to such "antiviral" compartments. To understand this enigma, we investigate the cross talk between PML-NB components and viral RCs to find the missing link connecting both compartments to promote efficient viral replication and gene expression. Taken together, the current concept is more intricate than originally believed, since viruses apparently take advantage of several specific PML-NB-associated proteins to promote productive infection. Simultaneously, they efficiently inhibit antiviral measures to maintain the viral infectious program. Our data provide evidence that SUMOylation of the viral RC marker protein E2A represents the basis of this virus-host interface and regulates various downstream events to support HAdV productive infection. These results are the basis of our current attempts to generate and screen for specific E2A SUMOylation inhibitors to constitute novel therapeutic approaches to limit and prevent HAdV-mediated diseases and mortality of immunosuppressed patients. Full Article
nuc Nucleic Acid-Sensing Toll-Like Receptors Play a Dominant Role in Innate Immune Recognition of Pneumococci By mbio.asm.org Published On :: 2020-03-24T01:31:01-07:00 ABSTRACT Streptococcus pneumoniae (or pneumococcus) is a highly prevalent human pathogen. Toll-like receptors (TLRs) function as immune sensors that can trigger host defenses against this bacterium. Defects in TLR-activated signaling pathways, including deficiency in the adaptor protein myeloid differentiation factor 88 (MyD88), are associated with markedly increased susceptibility to infection. However, the individual MyD88-dependent TLRs predominantly involved in antipneumococcal defenses have not been identified yet. Here we find that triple knockout mice simultaneously lacking TLR7, TLR9, and TLR13, which sense the presence of bacterial DNA (TLR9) and RNA (TLR7 and TLR13) in the phagolysosomes of phagocytic cells, display a phenotype that largely resembles that of MyD88-deficient mice and rapidly succumb to pneumococcal pneumonitis due to defective neutrophil influx into the lung. Accordingly, TLR7/9/13 triple knockout resident alveolar macrophages were largely unable to respond to pneumococci with the production of neutrophil-attracting chemokines and cytokines. Mice with single deficiencies of TLR7, TLR9, or TLR13 showed unaltered ability to control lung infection but were moderately more susceptible to encephalitis, in association with a decreased ability of microglia to mount cytokine responses in vitro. Our data point to a dominant, tissue-specific role of nucleic acid-sensing pathways in innate immune recognition of S. pneumoniae and also show that endosomal TLRs are largely capable of compensating for the absence of each other, which seems crucial to prevent pneumococci from escaping immune recognition. These results may be useful to develop novel strategies to treat infections by antibiotic-resistant pneumococci based on stimulation of the innate immune system. IMPORTANCE The pneumococcus is a bacterium that frequently causes infections in the lungs, ears, sinus cavities, and meninges. During these infections, body defenses are triggered by tissue-resident cells that use specialized receptors, such as Toll-like receptors (TLRs), to sense the presence of bacteria. We show here that pneumococci are predominantly detected by TLRs that are located inside intracellular vacuoles, including endosomes, where these receptors can sense the presence of nucleic acids released from ingested bacteria. Mice that simultaneously lacked three of these receptors (specifically, TLR7, TLR9, and TLR13) were extremely susceptible to lung infection and rapidly died after inhalation of pneumococci. Moreover, tissue-resident macrophages from these mice were impaired in their ability to respond to the presence of pneumococci by producing inflammatory mediators capable of recruiting polymorphonuclear leucocytes to infection sites. This information may be useful to develop drugs to treat pneumococcal infections, particularly those caused by antibiotic-resistant strains. Full Article
nuc Visualizing Association of the Retroviral Gag Protein with Unspliced Viral RNA in the Nucleus By mbio.asm.org Published On :: 2020-04-07T01:31:16-07:00 ABSTRACT Packaging of genomic RNA (gRNA) by retroviruses is essential for infectivity, yet the subcellular site of the initial interaction between the Gag polyprotein and gRNA remains poorly defined. Because retroviral particles are released from the plasma membrane, it was previously thought that Gag proteins initially bound to gRNA in the cytoplasm or at the plasma membrane. However, the Gag protein of the avian retrovirus Rous sarcoma virus (RSV) undergoes active nuclear trafficking, which is required for efficient gRNA encapsidation (L. Z. Scheifele, R. A. Garbitt, J. D. Rhoads, and L. J. Parent, Proc Natl Acad Sci U S A 99:3944–3949, 2002, https://doi.org/10.1073/pnas.062652199; R. Garbitt-Hirst, S. P. Kenney, and L. J. Parent, J Virol 83:6790–6797, 2009, https://doi.org/10.1128/JVI.00101-09). These results raise the intriguing possibility that the primary contact between Gag and gRNA might occur in the nucleus. To examine this possibility, we created a RSV proviral construct that includes 24 tandem repeats of MS2 RNA stem-loops, making it possible to track RSV viral RNA (vRNA) in live cells in which a fluorophore-conjugated MS2 coat protein is coexpressed. Using confocal microscopy, we observed that both wild-type Gag and a nuclear export mutant (Gag.L219A) colocalized with vRNA in the nucleus. In live-cell time-lapse images, the wild-type Gag protein trafficked together with vRNA as a single ribonucleoprotein (RNP) complex in the nucleoplasm near the nuclear periphery, appearing to traverse the nuclear envelope into the cytoplasm. Furthermore, biophysical imaging methods suggest that Gag and the unspliced vRNA physically interact in the nucleus. Taken together, these data suggest that RSV Gag binds unspliced vRNA to export it from the nucleus, possibly for packaging into virions as the viral genome. IMPORTANCE Retroviruses cause severe diseases in animals and humans, including cancer and acquired immunodeficiency syndromes. To propagate infection, retroviruses assemble new virus particles that contain viral proteins and unspliced vRNA to use as gRNA. Despite the critical requirement for gRNA packaging, the molecular mechanisms governing the identification and selection of gRNA by the Gag protein remain poorly understood. In this report, we demonstrate that the Rous sarcoma virus (RSV) Gag protein colocalizes with unspliced vRNA in the nucleus in the interchromatin space. Using live-cell confocal imaging, RSV Gag and unspliced vRNA were observed to move together from inside the nucleus across the nuclear envelope, suggesting that the Gag-gRNA complex initially forms in the nucleus and undergoes nuclear export into the cytoplasm as a viral ribonucleoprotein (vRNP) complex. Full Article
nuc Histidine-Triad Hydrolases Provide Resistance to Peptide-Nucleotide Antibiotics By mbio.asm.org Published On :: 2020-04-07T01:31:16-07:00 ABSTRACT The Escherichia coli microcin C (McC) and related compounds are potent Trojan horse peptide-nucleotide antibiotics. The peptide part facilitates transport into sensitive cells. Inside the cell, the peptide part is degraded by nonspecific peptidases releasing an aspartamide-adenylate containing a phosphoramide bond. This nonhydrolyzable compound inhibits aspartyl-tRNA synthetase. In addition to the efficient export of McC outside the producing cells, special mechanisms have evolved to avoid self-toxicity caused by the degradation of the peptide part inside the producers. Here, we report that histidine-triad (HIT) hydrolases encoded in biosynthetic clusters of some McC homologs or by standalone genes confer resistance to McC-like compounds by hydrolyzing the phosphoramide bond in toxic aspartamide-adenosine, rendering them inactive. IMPORTANCE Uncovering the mechanisms of resistance is a required step for countering the looming antibiotic resistance crisis. In this communication, we show how universally conserved histidine-triad hydrolases provide resistance to microcin C, a potent inhibitor of bacterial protein synthesis. Full Article
nuc Progressive supranuclear palsy and pawpaw By cp.neurology.org Published On :: 2020-04-06T12:45:20-07:00 Consider consumption of annonacin-containing plant products, including pawpaw, as a possible environmental risk factor for atypical parkinsonism. Full Article
nuc Heterogeneous Nuclear Ribonucleoprotein L Negatively Regulates Foot-and-Mouth Disease Virus Replication through Inhibition of Viral RNA Synthesis by Interacting with the Internal Ribosome Entry Site in the 5' Untranslated Region [Virus-Cell Interactio By jvi.asm.org Published On :: 2020-05-04T08:00:46-07:00 Upon infection, the highly structured 5' untranslated region (5' UTR) of picornavirus is involved in viral protein translation and RNA synthesis. As a critical element in the 5' UTR, the internal ribosome entry site (IRES) binds to various cellular proteins to function in the processes of picornavirus replication. Foot-and-mouth disease virus (FMDV) is an important member in the family Picornaviridae, and its 5' UTR contains a functional IRES element. In this study, the cellular heterogeneous nuclear ribonucleoprotein L (hnRNP L) was identified as an IRES-binding protein for FMDV by biotinylated RNA pulldown assays, mass spectrometry (MS) analysis, and determination of hnRNP L-IRES interaction regions. Further, we found that hnRNP L inhibited the growth of FMDV through binding to the viral IRES and that the inhibitory effect of hnRNP L on FMDV growth was not due to FMDV IRES-mediated translation, but to influence on viral RNA synthesis. Finally, hnRNP L was demonstrated to coimmunoprecipitate with RNA-dependent RNA polymerase (3Dpol) in an FMDV RNA-dependent manner in the infected cells. Thus, our results suggest that hnRNP L, as a critical IRES-binding protein, negatively regulates FMDV replication by inhibiting viral RNA synthesis, possibly by remaining in the replication complex. IMPORTANCE Picornaviruses, as a large family of human and animal pathogens, cause a bewildering array of disease syndromes. Many host factors are implicated in the pathogenesis of these viruses, and some proteins interact with the viral IRES elements to affect function. Here, we report for the first time that cellular hnRNP L specifically interacts with the IRES of the picornavirus FMDV and negatively regulates FMDV replication through inhibiting viral RNA synthesis. Further, our results showed that hnRNP L coimmunoprecipitates with FMDV 3Dpol in a viral RNA-dependent manner, suggesting that it may remain in the replication complex to function. The data presented here would facilitate further understanding of virus-host interactions and the pathogenesis of picornavirus infections. Full Article
nuc Loss of nucleus accumbens low-frequency fluctuations is a signature of chronic pain [Neuroscience] By www.pnas.org Published On :: 2020-05-05T10:31:24-07:00 Chronic pain is a highly prevalent disease with poorly understood pathophysiology. In particular, the brain mechanisms mediating the transition from acute to chronic pain remain largely unknown. Here, we identify a subcortical signature of back pain. Specifically, subacute back pain patients who are at risk for developing chronic pain exhibit... Full Article
nuc {alpha}-Synuclein filaments from transgenic mouse and human synucleinopathy-containing brains are maȷor seed-competent species [Molecular Bases of Disease] By www.jbc.org Published On :: 2020-05-08T03:41:14-07:00 Assembled α-synuclein in nerve cells and glial cells is the defining pathological feature of neurodegenerative diseases called synucleinopathies. Seeds of α-synuclein can induce the assembly of monomeric protein. Here, we used sucrose gradient centrifugation and transiently transfected HEK 293T cells to identify the species of α-synuclein from the brains of homozygous, symptomatic mice transgenic for human mutant A53T α-synuclein (line M83) that seed aggregation. The most potent fractions contained Sarkosyl-insoluble assemblies enriched in filaments. We also analyzed six cases of idiopathic Parkinson's disease (PD), one case of familial PD, and six cases of multiple system atrophy (MSA) for their ability to induce α-synuclein aggregation. The MSA samples were more potent than those of idiopathic PD in seeding aggregation. We found that following sucrose gradient centrifugation, the most seed-competent fractions from PD and MSA brains are those that contain Sarkosyl-insoluble α-synuclein. The fractions differed between PD and MSA, consistent with the presence of distinct conformers of assembled α-synuclein in these different samples. We conclude that α-synuclein filaments are the main driving force for amplification and propagation of pathology in synucleinopathies. Full Article
nuc Quantification of the affinities of CRISPR-Cas9 nucleases for cognate protospacer adȷacent motif (PAM) sequences [Molecular Biophysics] By www.jbc.org Published On :: 2020-05-08T03:41:14-07:00 The CRISPR/Cas9 nucleases have been widely applied for genome editing in various organisms. Cas9 nucleases complexed with a guide RNA (Cas9–gRNA) find their targets by scanning and interrogating the genomic DNA for sequences complementary to the gRNA. Recognition of the DNA target sequence requires a short protospacer adjacent motif (PAM) located outside this sequence. Given that the efficiency of target location may depend on the strength of interactions that promote target recognition, here we sought to compare affinities of different Cas9 nucleases for their cognate PAM sequences. To this end, we measured affinities of Cas9 nucleases from Streptococcus pyogenes, Staphylococcus aureus, and Francisella novicida complexed with guide RNAs (gRNAs) (SpCas9–gRNA, SaCas9–gRNA, and FnCas9–gRNA, respectively) and of three engineered SpCas9–gRNA variants with altered PAM specificities for short, PAM-containing DNA probes. We used a “beacon” assay that measures the relative affinities of DNA probes by determining their ability to competitively affect the rate of Cas9–gRNA binding to fluorescently labeled target DNA derivatives called “Cas9 beacons.” We observed significant differences in the affinities for cognate PAM sequences among the studied Cas9 enzymes. The relative affinities of SpCas9–gRNA and its engineered variants for canonical and suboptimal PAMs correlated with previous findings on the efficiency of these PAM sequences in genome editing. These findings suggest that high affinity of a Cas9 nuclease for its cognate PAM promotes higher genome-editing efficiency. Full Article
nuc Recent Approaches To Optimize Laboratory Assessment of Antinuclear Antibodies [Minireviews] By cvi.asm.org Published On :: 2017-12-05T08:00:30-08:00 The presence of antinuclear antibodies (ANAs) is a hallmark of a number of systemic autoimmune rheumatic diseases, and testing is usually performed as part of the initial diagnostic workup when suspicion of an underlying autoimmune disorder is high. The indirect immunofluorescence antibody (IFA) technique is the preferred method for detecting ANAs, as it demonstrates binding to specific intracellular structures within the cells, resulting in a number of staining patterns that are usually categorized based on the cellular components recognized and the degree of binding, as reflected by the fluorescence intensity or titer. As a screening tool, the ANA patterns can guide confirmatory testing useful in elucidating a specific clinical diagnosis or prognosis. However, routine use of ANA IFA testing as a global screening test is hampered by its labor-intensiveness, subjectivity, and limited diagnostic specificity, among other factors. This review focuses on current efforts to standardize the nomenclature of ANA patterns and on alternative methods for ANA determination, as well as on recent advances in image-based computer algorithms to automate IFA testing in clinical laboratories. Full Article
nuc Nucleostemin Modulates Outcomes of Hepatocellular Carcinoma via a Tumor Adaptive Mechanism to Genomic Stress By mcr.aacrjournals.org Published On :: 2020-05-04T05:40:21-07:00 Hepatocellular carcinomas (HCC) are adapted to survive extreme genomic stress conditions imposed by hyperactive DNA replication and genotoxic drug treatment. The underlying mechanisms remain unclear, but may involve intensified DNA damage response/repair programs. Here, we investigate a new role of nucleostemin (NS) in allowing HCC to survive its own malignancy, as NS was previously shown to promote liver regeneration via a damage repair mechanism. We first established that a higher NS transcript level correlates with high-HCC grades and poor prognostic signatures, and is an independent predictor of shorter overall and progression-free survival specifically for HCC and kidney cancer but not for others. Immunostaining confirmed that NS is most abundantly expressed in high-grade and metastatic HCCs. Genome-wide analyses revealed that NS is coenriched with MYC target and homologous recombination (HR) repair genes in human HCC samples and functionally intersects with those involved in replication stress response and HR repair in yeasts. In support, NS-high HCCs are more reliant on the replicative/oxidative stress response pathways, whereas NS-low HCCs depend more on the mTOR pathway. Perturbation studies showed NS function in protecting human HCC cells from replication- and drug-induced DNA damage. Notably, NS depletion in HCC cells increases the amounts of physical DNA damage and cytosolic double-stranded DNA, leading to a reactive increase of cytokines and PD-L1. This study shows that NS provides an essential mechanism for HCC to adapt to high genomic stress for oncogenic maintenance and propagation. NS deficiency sensitizes HCC cells to chemotherapy but also triggers tumor immune responses. Implications: HCC employs a novel, nucleostemin (NS)-mediated-mediated adaptive mechanism to survive high genomic stress conditions, a deficiency of which sensitizes HCC cells to chemotherapy but also triggers tumor immune responses. Full Article
nuc Hepatic Transporter Alterations by Nuclear Receptor Agonist T0901317 in Sandwich-Cultured Human Hepatocytes: Proteomic Analysis and PBPK Modeling to Evaluate Drug-Drug Interaction Risk [Metabolism, Transport, and Pharmacogenomics] By jpet.aspetjournals.org Published On :: 2020-04-21T06:02:31-07:00 In vitro approaches for predicting drug-drug interactions (DDIs) caused by alterations in transporter protein regulation are not well established. However, reports of transporter regulation via nuclear receptor (NR) modulation by drugs are increasing. This study examined alterations in transporter protein levels in sandwich-cultured human hepatocytes (SCHH; n = 3 donors) measured by liquid chromatography–tandem mass spectrometry–based proteomic analysis after treatment with N-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]-N-(2,2,2-trifluoroethyl)benzenesulfonamide (T0901317), the first described synthetic liver X receptor agonist. T0901317 treatment (10 μM, 48 hours) decreased the levels of organic cation transporter (OCT) 1 (0.22-, 0.43-, and 0.71-fold of control) and organic anion transporter (OAT) 2 (0.38-, 0.38-, and 0.53-fold of control) and increased multidrug resistance protein (MDR) 1 (1.37-, 1.48-, and 1.59-fold of control). The induction of NR downstream gene expression supports the hypothesis that T0901317 off-target effects on farnesoid X receptor and pregnane X receptor activation are responsible for the unexpected changes in OCT1, OAT2, and MDR1. Uptake of the OCT1 substrate metformin in SCHH was decreased by T0901317 treatment. Effects of decreased OCT1 levels on metformin were simulated using a physiologically-based pharmacokinetic (PBPK) model. Simulations showed a clear decrease in metformin hepatic exposure resulting in a decreased pharmacodynamic effect. This DDI would not be predicted by the modest changes in simulated metformin plasma concentrations. Altogether, the current study demonstrated that an approach combining SCHH, proteomic analysis, and PBPK modeling is useful for revealing tissue concentration–based DDIs caused by unexpected regulation of hepatic transporters by NR modulators. SIGNIFICANCE STATEMENT This study utilized an approach combining sandwich-cultured human hepatocytes, proteomic analysis, and physiologically based pharmacokinetic modeling to evaluate alterations in pharmacokinetics (PK) and pharmacodynamics (PD) caused by transporter regulation by nuclear receptor modulators. The importance of this approach from a mechanistic and clinically relevant perspective is that it can reveal drug-drug interactions (DDIs) caused by unexpected regulation of hepatic transporters and enable prediction of altered PK and PD changes, especially for tissue concentration–based DDIs. Full Article
nuc ProPSMA: A Callout to the Nuclear Medicine Community to Change Practices with Prospective, High-Quality Data By jnm.snmjournals.org Published On :: 2020-05-01T06:31:37-07:00 Full Article
nuc The Standard of Care: From Nuclear Radiology to Nuclear Medicine By jnm.snmjournals.org Published On :: 2020-05-01T06:31:37-07:00 Full Article
nuc Incidental Findings Suggestive of COVID-19 in Asymptomatic Patients Undergoing Nuclear Medicine Procedures in a High-Prevalence Region By jnm.snmjournals.org Published On :: 2020-05-01T06:31:37-07:00 Infection with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may remain asymptomatic, leading to under-recognition of the related disease, coronavirus disease, 2019 (COVID-19), and to incidental findings in nuclear imaging procedures performed for standard clinical indications. Here, we report about our local experience in a region with high COVID-19 prevalence and dynamically increasing infection rates. Methods: Within the 8-d period of March 16–24, 2020, hybrid imaging studies of asymptomatic patients who underwent 18F-FDG PET/CT or 131I SPECT/CT for standard oncologic indications at our institution in Brescia, Italy, were analyzed for findings suggestive of COVID-19. The presence, radiologic features, and metabolic activity of interstitial pneumonia were identified, correlated with the subsequent short-term clinical course, and described in a case series. Results: Six of 65 patients (9%) who underwent PET/CT for various malignancies showed unexpected signs of interstitial pneumonia on CT and elevated regional 18F-FDG avidity. Additionally, 1 of 12 patients who received radioiodine for differentiated thyroid carcinoma also showed interstitial pneumonia on SPECT/CT. Five of 7 patients had subsequent proof of COVID-19 by reverse-transcriptase polymerase chain reaction. The remaining 2 patients were not tested immediately but underwent quarantine and careful monitoring. Conclusion: Incidental findings suggestive of COVID-19 may not be infrequent in hybrid imaging of asymptomatic patients in regions with an expansive spread of SARS-CoV-2. Nuclear medicine services should prepare accordingly. Full Article
nuc Nuclear Medicine Operations in the Times of COVID-19: Strategies, Precautions, and Experiences By jnm.snmjournals.org Published On :: 2020-05-01T06:31:37-07:00 Full Article