The CTGF -945GC polymorphism is not associated with plasma CTGF and does not predict nephropathy or outcome in type 1 diabetes

The -945GC polymorphism (rs6918698) in the connective tissue growth factor gene promoter (CTGF/CCN-2) has been associated with end organ damage in systemic sclerosis. Because CTGF is important in progression of diabetic kidney disease, we investigated whether the -945GC polymorphism is associated with plasma CTGF level and outcome in type 1 diabetes

Hepatoviruses promote very-long-chain fatty acid and sphingolipid synthesis for viral RNA replication and quasi-enveloped virus release

Virus-induced changes in host lipid metabolism are an important but poorly understood aspect of viral pathogenesis. By combining nontargeted lipidomics analyses of infected cells and purified extracellular quasi-enveloped virions with high-throughput RNA sequencing and genetic depletion studies, we show that hepatitis A virus, an hepatotropic picornavirus, broadly manipulates the host cell lipid environment, enhancing synthesis of ceramides and other sphingolipids and transcriptionally activating acyl–coenzyme A synthetases and fatty acid elongases to import and activate long-chain fatty acids for entry into the fatty acid elongation cycle. Phospholipids with very-long-chain acyl tails (>C22) are essential for genome replication, whereas increases in sphingolipids support assembly and release of quasi-enveloped virions wrapped in membranes highly enriched for sphingomyelin and very-long-chain ceramides. Our data provide insight into how a pathogenic virus alters lipid flux in infected hepatocytes and demonstrate a distinction between lipid species required for viral RNA synthesis versus nonlytic quasi-enveloped virus release

Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels.

Elevated serum urate levels can cause gout, an excruciating disease with suboptimal treatment. Previous GWAS identified common variants with modest effects on serum urate. Here we report large-scale whole-exome sequencing association studies of serum urate and kidney function among ≤19,517 European ancestry and African-American individuals. We identify aggregate associations of low-frequency damaging variants in the urate transporters SLC22A12 (URAT1; p = 1.3 × 10 <sup>-56</sup> ) and SLC2A9 (p = 4.5 × 10 <sup>-7</sup> ). Gout risk in rare SLC22A12 variant carriers is halved (OR = 0.5, p = 4.9 × 10 <sup>-3</sup> ). Selected rare variants in SLC22A12 are validated in transport studies, confirming three as loss-of-function (R325W, R405C, and T467M) and illustrating the therapeutic potential of the new URAT1-blocker lesinurad. In SLC2A9, mapping of rare variants of large effects onto the predicted protein structure reveals new residues that may affect urate binding. These findings provide new insights into the genetic architecture of serum urate, and highlight molecular targets in SLC22A12 and SLC2A9 for lowering serum urate and preventing gout

Preclinical Evaluation of Oncolytic Vaccinia Virus for Therapy of Canine Soft Tissue Sarcoma

Virotherapy using oncolytic vaccinia virus (VACV) strains is one promising new strategy for canine cancer therapy. In this study we describe the establishment of an in vivo model of canine soft tissue sarcoma (CSTS) using the new isolated cell line STSA-1 and the analysis of the virus-mediated oncolytic and immunological effects of two different Lister VACV LIVP1.1.1 and GLV-1h68 strains against CSTS. Cell culture data demonstrated that both tested VACV strains efficiently infected and destroyed cells of the canine soft tissue sarcoma line STSA-1. In addition, in our new canine sarcoma tumor xenograft mouse model, systemic administration of LIVP1.1.1 or GLV-1h68 viruses led to significant inhibition of tumor growth compared to control mice. Furthermore, LIVP1.1.1 mediated therapy resulted in almost complete tumor regression and resulted in long-term survival of sarcoma-bearing mice. The replication of the tested VACV strains in tumor tissues led to strong oncolytic effects accompanied by an intense intratumoral infiltration of host immune cells, mainly neutrophils. These findings suggest that the direct viral oncolysis of tumor cells and the virus-dependent activation of tumor-associated host immune cells could be crucial parts of anti-tumor mechanism in STSA-1 xenografts. In summary, the data showed that both tested vaccinia virus strains and especially LIVP1.1.1 have great potential for effective treatment of CSTS

Fluctuations in measured radioactive decay rates inside a modified Faraday cage: Correlations with space weather

[EN] For several years, reports have been published about fluctuations in measured radioactive decay time-series and in some instances linked to astrophysical as well as classical environmental influences. Anomalous behaviors of radioactive decay measurement and measurement of capacitance inside and outside a modified Faraday cage were documented by our group in previous work. In the present report, we present an in-depth analysis of our measurement with regard to possible correlations with space weather, i.e. the geomagnetic activity (GMA) and cosmic-ray activity (CRA). Our analysis revealed that the decay and capacitance time-series are statistically significantly correlated with GMA and CRA when specific conditions are met. The conditions are explained in detail and an outlook is given on how to further investigate this important finding. Our discovery is relevant for all researchers investigating radioactive decay measurements since they point out that the space weather condition during the measurement is relevant for partially explaining the observed variability.This work has been partially financed by: grant no. 20170764 (Equipos de deteccion, regulacion e informacion en el sector de los sistemas inteligentes de transporte (ITS). Nuevos modelos y ensayos de compatibilidad y verificacion de funcionamiento) (Spain), by grant no. RTI2018-102256-B-I00 (Spain), by the Generalitat Valenciana (Spain) under project Bioingenieria de las Radiaciones Ionizantes. Biorad (PROMETEO/2018/035) and the project MEMO RADION (IDIFEDER/2018/038) co-financed by the Programa Operativo del Fondo Social Europeo 2014-2020", and by grant No.075-00845-20-01 (Russia).Milián-Sánchez, V.; Scholkmann, F.; Fernández De Córdoba, P.; Mocholí Salcedo, A.; Mocholí-Belenguer, F.; Iglesias-Martínez, ME.; Castro-Palacio, JC.... (2020). Fluctuations in measured radioactive decay rates inside a modified Faraday cage: Correlations with space weather. Scientific Reports. 10(1):1-12. https://doi.org/10.1038/s41598-020-64497-0S112101Milián-Sánchez, V., Mocholí-Salcedo, A., Milián, C., Kolombet, V. A. & Verdú, G. Anomalous effects on radiation detectors and capacitance measurements inside a modified Faraday cage. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment 828, 210–228 (2016).G. F. Knoll Radiation Detection and Measurement, 4th Edition. (Wiley, 2010).Jenkins, J. H., Mundy, D. W. & Fischbach, E. Analysis of environmental influences in nuclear half-life measurements exhibiting time-dependent decay rates. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment 620, 332–342 (2010).Jenkins, J. H. et al. 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On the claim of modulations in radon decay and their association with solar rotation. Astroparticle Physics 97, 38–45 (2018).S. Pommé, K. Kossert, O. Nähle On the Claim of Modulations in 36Cl Beta Decay and Their Association with Solar Rotation. Solar Physics 292 (2017).Pommé, S. et al. Is decay constant? Applied Radiation and Isotopes 134, 6–12 (2018).Bellotti, E., Broggini, C., Di Carlo, G., Laubenstein, M. & Menegazzo, R. Search for time modulations in the decay constant of 40 K and 226 Ra at the underground Gran Sasso Laboratory. Physics Letters B 780, 61–65 (2018).Borrello, J. A., Wuosmaa, A. & Watts, M. Non-dependence of nuclear decay rates of 123 I and 99m Tc on Earth-Sun distance. Applied Radiation and Isotopes 132, 189–194 (2018).Sturrock, P. A., Steinitz, G., Fischbach, E., Parkhomov, A. & Scargle, J. D. Analysis of beta-decay data acquired at the Physikalisch-Technische Bundesanstalt: Evidence of a solar influence. Astroparticle Physics 84, 8–14 (2016).Stancil, D. D., Balci Yegen, S., Dickey, D. A. & Gould, C. R. Search for possible solar influences in Ra-226 decays. Results in Physics 7, 385–406 (2017).P. A. Sturrock, G. Steinitz & E. Fischbach Analysis of Ten Years of Radon-Chain Decay Measurements: Evidence of Solar Influences and Inferences Concerning Solar Internal Structure and the Role of Neutrinos. arXiv:1705.03010 [astro-ph.SR], (2017).Sturrock, P. A., Steinitz, G. & Fischbach, E. Concerning the variability of nuclear decay rates: Rebuttal of an article by Pomme et al. [1]. Astroparticle Physics 98, 9–12 (2018).Pommé, S., Lutter, G., Marouli, M., Kossert, K. & Nähle, O. A reply to the rebuttal by Sturrock et al. Astroparticle Physics 107, 22–25 (2019).S. Pommé, Solar influence on radon decay rates: irradiance or neutrinos? The European Physical Journal C. 79 (2019).Barnes, V. E. et al. Upper limits on perturbations of nuclear decay rates induced by reactor electron antineutrinos. 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Coreceptor Usage by HIV-1 and HIV-2 Primary Isolates: The Relevance of CCR8 Chemokine Receptor as an Alternative Coreceptor

The human immunodeficiency virus replication cycle begins by sequential interactions between viral envelope glycoproteins with CD4 molecule and a member of the seven-transmembrane, G-protein-coupled, receptors' family (coreceptor). In this report we focused on the contribution of CCR8 as alternative coreceptor for HIV-1 and HIV-2 isolates. We found that this coreceptor was efficiently used not only by HIV-2 but particularly by HIV-1 isolates. We demonstrate that CXCR4 usage, either alone or together with CCR5 and/or CCR8, was more frequently observed in HIV-1 than in HIV-2 isolates. Directly related to this is the finding that the non-usage of CXCR4 is significantly more common in HIV-2 isolates; both features could be associated with the slower disease progression generally observed in HIV-2 infected patients. The ability of some viral isolates to use alternative coreceptors besides CCR5 and CXCR4 could further impact on the efficacy of entry inhibitor therapy and possibly also in HIV pathogenesis

The New Era of Physio-Logging and Their Grand Challenges.

International audienc

HIV-2 interaction with cell coreceptors: amino acids within the V1/V2 region of viral envelope are determinant for CCR8, CCR5 and CXCR4 usage

© 2014 Santos-Costa et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background: Human immunodeficiency virus 1 and 2 (HIV-1 and HIV-2) use cellular receptors in distinct ways. Besides a more promiscuous usage of coreceptors by HIV-2 and a more frequent detection of CD4-independent HIV-2 isolates, we have previously identified two HIV-2 isolates (HIV-2MIC97 and HIV-2MJC97) that do not use the two major HIV coreceptors: CCR5 and CXCR4. All these features suggest that in HIV-2 the Env glycoprotein subunits may have a different structural organization enabling distinct - although probably less efficient - interactions with cellular receptors. Results: By infectivity assays using GHOST cell line expressing CD4 and CCR8 and blocking experiments using CCR8-specific ligand, I-309, we show that efficient replication of HIV-2MIC97 and HIV-2MJC97 requires the presence of CCR8 at plasma cell membrane. Additionally, we disclosed the determinants of chemokine receptor usage at the molecular level, and deciphered the amino acids involved in the usage of CCR8 (R8 phenotype) and in the switch from CCR8 to CCR5 or to CCR5/CXCR4 usage (R5 or R5X4 phenotype). The data obtained from site-directed mutagenesis clearly indicates that the main genetic determinants of coreceptor tropism are located within the V1/V2 region of Env surface glycoprotein of these two viruses. Conclusions: We conclude that a viral population able to use CCR8 and unable to infect CCR5 or CXCR4-positive cells, may exist in some HIV-2 infected individuals during an undefined time period, in the course of the asymptomatic stage of infection. This suggests that in vivo alternate molecules might contribute to HIV infection of natural target cells, at least under certain circumstances. Furthermore we provide direct and unequivocal evidence that the usage of CCR8 and the switch from R8 to R5 or R5X4 phenotype is determined by amino acids located in the base and tip of V1 and V2 loops of HIV-2 Env surface glycoprotein.This work was supported by grants from: Fundação para a Ciência e Tecnologia (FCT; PPCDT/SAU-IMI/55726/2004); Fundação para a Ciência e Tecnologia and Ministério da Saúde de Portugal (VIH/SAU/0006/2011); and from Gilead Sciences Portugal (Programa Gilead Génese).info:eu-repo/semantics/publishedVersio

Assembly PCR synthesis of optimally designed, compact, multi-responsive promoters suited to gene therapy application

MRC-DTA studentship award British Pharmacological Society Integrative Awar