Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp14 RNA cap methyltransferase

The COVID-19 pandemic has presented itself as one of the most critical public health challenges of the century, with SARS-CoV-2 being the third member of the Coronaviridae family to cause a fatal disease in humans. There is currently only one antiviral compound, remdesivir, that can be used for the treatment of COVID-19. To identify additional potential therapeutics, we investigated the enzymatic proteins encoded in the SARS-CoV-2 genome. In this study, we focussed on the viral RNA cap methyltransferases, which play key roles in enabling viral protein translation and facilitating viral escape from the immune system. We expressed and purified both the guanine-N7 methyltransferase nsp14, and the nsp16 2′-O-methyltransferase with its activating cofactor, nsp10. We performed an in vitro high-throughput screen for inhibitors of nsp14 using a custom compound library of over 5000 pharmaceutical compounds that have previously been characterised in either clinical or basic research. We identified four compounds as potential inhibitors of nsp14, all of which also showed antiviral capacity in a cell-based model of SARS-CoV-2 infection. Three of the four compounds also exhibited synergistic effects on viral replication with remdesivir

MiR-223 Suppresses Cell Proliferation by Targeting IGF-1R

To study the roles of microRNA-223 (miR-223) in regulation of cell growth, we established a miR-223 over-expression model in HeLa cells infected with miR-223 by Lentivirus pLL3.7 system. We observed in this model that miR-223 significantly suppressed the proliferation, growth rate, colony formation of HeLa cells in vitro, and in vivo tumorigenicity or tumor formation in nude mice. To investigate the mechanisms involved, we scanned and examined the potential and putative target molecules of miR-223 by informatics, quantitative PCR and Western blot, and found that insulin-like growth factor-1 receptor (IGF-1R) was the functional target of miR-223 inhibition of cell proliferation. Targeting IGF-1R by miR-223 was not only seen in HeLa cells, but also in leukemia and hepatoma cells. The downstream pathway, Akt/mTOR/p70S6K, to which the signal was mediated by IGF-1R, was inhibited as well. The relative luciferase activity of the reporter containing wild-type 3′UTR(3′untranslated region) of IGF-1R was significantly suppressed, but the mutant not. Silence of IGF-1R expression by vector-based short hairpin RNA resulted in the similar inhibition with miR-223. Contrarily, rescued IGF-1R expression in the cells that over-expressed miR-223, reversed the inhibition caused by miR-223 via introducing IGF-1R cDNA that didn't contain the 3′UTR. Meanwhile, we also noted that miR-223 targeted Rasa1, but the downstream molecules mediated by Rasa1 was neither targeted nor regulated. Therefore we believed that IGF-1R was the functional target for miR-223 suppression of cell proliferation and its downstream PI3K/Akt/mTOR/p70S6K pathway suppressed by miR-223 was by targeting IGF-1R

PRODUÇÃO ARTESANAL ENTRE OS WAI-WAI EM ESPAÇOS DE UMA CASA DE APOIO A SAÚDE INDÍGENA

Os povos indígenas possuem pelo Sistema Único de Saúde (SUS) o direito a serviços específicos da rede de atenção à saúde, entre eles polos administrativos e casas de apoio à saúde. No caso da etnia Wai-wai, estes recebem atendimento multiprofissional de saúde pela Casa de Apoio de Saúde Indígena de Oriximiná, município do oeste do Pará. São territórios, em geral, em um contexto biomédico, mas que se direcionam por práticas interculturais conforme preconizado pela Política Nacional de Atenção a Saúde dos Povos Indígenas..

The Long Distance Contribution to D→πl+l−D\to\pi l^+l^-

We calculate the long distance contribution to $D^{+,0}\to\pi^{+,0}l^+l^-$ decays by the use of a vector meson dominance model, in which the $\phi$-meson plays the central role. The branching ratios obtained are $10^{-6}$ and a few times $10^{-7}$ for the resonance and non-resonance regions respectively. The analysis includes a calculation of $D^+\to\pi^+\phi$, consistent with the experimental value.Comment: Latex file, 10 pages, no figur

International Veterinary Epilepsy Task Force recommendations for a veterinary epilepsy-specific MRI protocol

Epilepsy is one of the most common chronic neurological diseases in veterinary practice. Magnetic resonance imaging (MRI) is regarded as an important diagnostic test to reach the diagnosis of idiopathic epilepsy. However, given that the diagnosis requires the exclusion of other differentials for seizures, the parameters for MRI examination should allow the detection of subtle lesions which may not be obvious with existing techniques. In addition, there are several differentials for idiopathic epilepsy in humans, for example some focal cortical dysplasias, which may only apparent with special sequences, imaging planes and/or particular techniques used in performing the MRI scan. As a result, there is a need to standardize MRI examination in veterinary patients with techniques that reliably diagnose subtle lesions, identify post-seizure changes, and which will allow for future identification of underlying causes of seizures not yet apparent in the veterinary literature. There is a need for a standardized veterinary epilepsy-specific MRI protocol which will facilitate more detailed examination of areas susceptible to generating and perpetuating seizures, is cost efficient, simple to perform and can be adapted for both low and high field scanners. Standardisation of imaging will improve clinical communication and uniformity of case definition between research studies. A 6–7 sequence epilepsy-specific MRI protocol for veterinary patients is proposed and further advanced MR and functional imaging is reviewed

Morphology-Controllable Synthesis of CeO2on a Pt Electrode

Nanoscale cerium dioxides with shape of nanoparticles, nanorods, and nanotubes were electrochemically synthesized. The morphology of CeO2was modulated by changing electrode potential and potential direction. CeO2nanorods and CeO2nanotubes were synthesized via the potentiostatic and cyclic voltammeteric methods, respectively. The morphology and structure of the obtained CeO2were characterized by field emission scanning electron microscope (FESEM) and X-ray diffraction (XRD). A possible formation mechanism has been suggested to illuminate the relationship between the preparation condition and the morphology of CeO2

APOE ε2 resilience for Alzheimer’s disease is mediated by plasma lipid species: Analysis of three independent cohort studies

Introduction The apolipoprotein E (APOE) genotype is the strongest genetic risk factor for late-onset Alzheimer\u27s disease. However, its effect on lipid metabolic pathways, and their mediating effect on disease risk, is poorly understood. Methods We performed lipidomic analysis on three independent cohorts (the Australian Imaging, Biomarkers and Lifestyle [AIBL] flagship study, n = 1087; the Alzheimer\u27s Disease Neuroimaging Initiative [ADNI] 1 study, n = 819; and the Busselton Health Study [BHS], n = 4384), and we defined associations between APOE ε2 and ε4 and 569 plasma/serum lipid species. Mediation analysis defined the proportion of the treatment effect of the APOE genotype mediated by plasma/serum lipid species. Results A total of 237 and 104 lipid species were associated with APOE ε2 and ε4, respectively. Of these 68 (ε2) and 24 (ε4) were associated with prevalent Alzheimer\u27s disease. Individual lipid species or lipidomic models of APOE genotypes mediated up to 30% and 10% of APOE ε2 and ε4 treatment effect, respectively. Discussion Plasma lipid species mediate the treatment effect of APOE genotypes on Alzheimer\u27s disease and as such represent a potential therapeutic target

Measurement of Υ\Upsilon(1S+2S+3S) production in pp++pp and Au++Au collisions at sNN=200\sqrt{s_{_{NN}}}=200 GeV

Measurements of bottomonium production in heavy ion and $p$$+$$p$ collisions at the Relativistic Heavy Ion Collider (RHIC) are presented. The inclusive yield of the three $\Upsilon$ states, $\Upsilon(1S+2S+3S)$, was measured in the PHENIX experiment via electron-positron decay pairs at midrapidity for Au$+$Au and $p$$+$$p$ collisions at $\sqrt{s_{_{NN}}}=200$ GeV. The $\Upsilon(1S+2S+3S)\rightarrow e^+e^-$ differential cross section at midrapidity was found to be $B_{\rm ee} d\sigma/dy =$ 108 $\pm$ 38 (stat) $\pm$ 15(syst) $\pm$ 11 (luminosity) pb in $p$$+$$p$ collisions. The nuclear modification factor in the 30\% most central Au$+$Au collisions indicates a suppression of the total $\Upsilon$ state yield relative to the extrapolation from $p$$+$$p$ collision data. The suppression is consistent with measurements made by STAR at RHIC and at higher energies by the CMS experiment at the Large Hadron Collider.Comment: 506 authors, 15 pages, 17 figures, and 7 tables. v3 is as accepted by Phys. Rev. C. v2 has changes to text and figures, plus additional authors. Published version will be at http://www.phenix.bnl.gov/phenix/WWW/info/pp1/1NN/ Plain text data tables are (or will be) at http://www.phenix.bnl.gov/papers.htm