Immunomodulatory oligonucleotide IMT504: effects on mesenchymal stem cells as a first-in-class immunoprotective/immunoregenerative therapy

The immune responses of humans and animals to insults (i.e., infections, traumas, tumoral transformation and radiation) are based on an intricate network of cells and chemical messengers. Abnormally high inflammation immediately after insult or abnormally prolonged pro-inflammatory stimuli bringing about chronic inflammation can lead to life-threatening or severely debilitating diseases. Mesenchymal stem cell (MSC) transplant has proved to be an effective therapy in preclinical studies which evaluated a vast diversity of inflammatory conditions. MSCs lead to resolution of inflammation, preparation for regeneration and actual regeneration, and then ultimate return to normal baseline or homeostasis. However, in clinical trials of transplanted MSCs, the expectations of great medical benefit have not yet been fulfilled. As a practical alternative to MSC transplant, a synthetic drug with the capacity to boost endogenous MSC expansion and/or activation may also be effective. Regarding this, IMT504, the prototype of a major class of immunomodulatory oligonucleotides, induces in vivo expansion of MSCs, resulting in a marked improvement in preclinical models of neuropathic pain, osteoporosis, diabetes and sepsis. IMT504 is easily manufactured and has an excellent preclinical safety record. In the small number of patients studied thus far, IMT504 has been well-tolerated, even at very high dosage. Further clinical investigation is necessary to demonstrate the utility of IMT504 for resolution of inflammation and regeneration in a broad array of human diseases that would likely benefit from an immunoprotective/immunoregenerative therapy.Fil: Zorzopulos, Jorge. Immunotech; ArgentinaFil: Opal, Steven M.. Memorial Hospital of Rhode Island; Estados Unidos. Alpert Medical School; Estados UnidosFil: Hernando Insúa, Andrés. Fundación Pablo Cassara; ArgentinaFil: Rodriguez, Juan M.. Fundación Pablo Cassara; ArgentinaFil: Elías, Fernanda. Fundación Pablo Cassara; ArgentinaFil: Fló, Juan. Immunotech; ArgentinaFil: López, Ricardo A.. Imunotech; ArgentinaFil: Chasseing, Norma Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Lux, Victoria Adela R.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Coronel, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Franco, Raul. Imunotech; ArgentinaFil: Montaner, Alejandro D. Fundación Pablo Cassara; ArgentinaFil: Horn, David L. David Horn Llc; Estados Unido

Total absorption gamma-ray spectroscopy study of the β-decay of 186Hg

7 pags., 9 figs., 1 tab.The Gamow-Teller strength distribution of the decay of Hg into Au has been determined for the first time using the total absorption gamma spectroscopy technique and has been compared with theoretical QRPA calculations using the SLy4 Skyrme force. The measured Gamow-Teller strength distribution and the half-life are described by mixing oblate and prolate configurations independently in the parent and daughter nuclei. In this theoretical framework the best description of the experimental beta strength is obtained with dominantly prolate components for both parent Hg and daughter Au. The approach also allowed us to determine an upper limit of the oblate component in the parent state. The complexity of the analysis required the development of a new approach in the analysis of the X-ray gated total absorption spectrum.This work was supported by Spanish Ministerio de Economía y Competitividad under grants FPA2011-24553, FPA2014-52823-C2-1-P, FPA2017-83946-C2-1-P, FPA2017-87568-P, Ministerio de Ciencia e Innovación grants PID2019-104714GB-C21 and RTI2018-098868-B-100, program Severo Ochoa (SEV-2014-0398), ENSAR (grant 262010) and by the European Union Horizon 2020 research and innovation programme under Grant Agreement No. 654002. S.E.A.O. thanks the support of CPAN Consolider-Ingenio 2010 Programme CSD2007-00042 grant. E.G. acknowledges support from TÜBITAK 2219 Abroad Research Fellowship Programme. R.B.C. acknowledges support by the Max-Planck-Partner group. Support from the technical staff and engineers of ISOLDE-CERN is acknowl- edged. W.G. acknowledges the support of STFC (UK) council grant ST/P005314/1. V.G. acknowledges the support of the National Science Center, Poland, under Contract No. 2019/35/D/ST2/02081. This work was also supported by the National Research, Development and Innovation Fund of Hungary, financed under the K18 funding scheme with Projects No. K 128729 and NN128072. P.S. acknowledges support from MCI/AEI/FEDER, UE (Spain) under grant PGC2018-093636-B-I0

Babelomics 5.0: functional interpretation for new generations of genomic data

This article has been accepted for publication in Nucleic Acids Research Published by Oxford University Press.Babelomics has been running for more than one decade offering a user-friendly interface for the functional analysis of gene expression and genomic data. Here we present its fifth release, which includes support for Next Generation Sequencing data including gene expression (RNA-seq), exome or genome resequencing. Babelomics has simplified its interface, being now more intuitive. Improved visualization options, such as a genome viewer as well as an interactive network viewer, have been implemented. New technical enhancements at both, client and server sides, makes the user experience faster and more dynamic. Babelomics offers user-friendly access to a full range of methods that cover: (i) primary data analysis, (ii) a variety of tests for different experimental designs and (iii) different enrichment and network analysis algorithms for the interpretation of the results of such tests in the proper functional context. In addition to the public server, local copies of Babelomics can be downloaded and installed. Babelomics is freely available at: http://www.babelomics.org.Spanish Ministry of Economy and Competitiveness [BIO2011-27069], Conselleria d'Educacio of the Valencian Community [PROMETEOII/2014/025]; EU FP7-PEOPLE Project MLPM [316861]; Fundació la Marató TV3 [151/C/2013]. Funding for open access charge: Spanish Ministry of Economy and Competitiveness [BIO2011-27069]

Serum tissue inhibitor of matrix metalloproteinase-1 levels are associated with mortality in patients with malignant middle cerebral artery infarction

Background: In the last years, circulating matrix metalloproteinases (MMP)-9 levels have been associated with functional outcome in ischemic stroke patients. However the prognostic value of circulating levels of tissue inhibitor of matrix metalloproteinases (TIMP)-1 and MMP-10 in functional outcome of ischemic stroke patients has been scarcely studied. In addition, to our knowledge, serum MMP-9, MMP-10 and TIMP-1 levels in patients with malignant middle cerebral artery infarction (MMCAI) for mortality prediction have not been studied, and these were the objectives of this study. Methods: This was a multicenter, observational and prospective study carried out in six Spanish Intensive Care Units. We included patients with severe MMCAI defined as Glasgow Coma Scale (GCS) lower than 9. We measured circulating levels of MMP-9, MMP-10, TIMP-1, in 50 patients with severe MMCAI at diagnosis and in 50 healthy subjects. Endpoint was 30-day mortality. Results: Patients with severe MMCAI showed higher serum levels of MMP-9 (p = 0.001), MMP-10 (p 239 ng/mL are associated with 30-day mortality (OR = 5.82; 95 % CI = 1.37-24.73; P = 0.02) controlling for GCS and age. The area under the curve for TIMP-1 as predictor of 30-day mortality was 0.81 (95 % CI = 0.67-0.91; P < 0.001). We found an association between circulating levels of TIMP-1 and MMP-10 (rho = 0.45; P = 0.001), plasminogen activator inhibitor (PAI)-1 (rho = 0.53; P < 0.001), and tumor necrosis factor (TNF)-alpha (rho = 0.70; P < 0.001). Conclusions: The most relevant and new findings of our study, were that serum TIMP-1 levels in MMCAI patients were associated with mortality, and could be used as a prognostic biomarker of mortality in MMCAI patients

The transcriptomics of an experimentally evolved plant-virus interaction

[EN] Models of plant-virus interaction assume that the ability of a virus to infect a host genotype depends on the matching between virulence and resistance genes. Recently, we evolved tobacco etch potyvirus (TEV) lineages on different ecotypes of Arabidopsis thaliana, and found that some ecotypes selected for specialist viruses whereas others selected for generalists. Here we sought to evaluate the transcriptomic basis of such relationships. We have characterized the transcriptomic responses of five ecotypes infected with the ancestral and evolved viruses. Genes and functional categories differentially expressed by plants infected with local TEV isolates were identified, showing heterogeneous responses among ecotypes, although significant parallelism existed among lineages evolved in the same ecotype. Although genes involved in immune responses were altered upon infection, other functional groups were also pervasively over-represented, suggesting that plant resistance genes were not the only drivers of viral adaptation. Finally, the transcriptomic consequences of infection with the generalist and specialist lineages were compared. Whilst the generalist induced very similar perturbations in the transcriptomes of the different ecotypes, the perturbations induced by the specialist were divergent. Plant defense mechanisms were activated when the infecting virus was specialist but they were down-regulated when infecting with generalist.We thank Francisca de la Iglesia and Paula Agudo for excellent technical assistance and our labmates for useful discussions and suggestions. 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PATJ Low Frequency Variants Are Associated with Worse Ischemic Stroke Functional Outcome: A Genome-Wide Meta-Analysis

RATIONALE: Ischemic stroke is among the leading causes of adult disability. Part of the variability in functional outcome after stroke has been attributed to genetic factors but no locus has been consistently associated with stroke outcome. OBJECTIVE: Our aim was to identify genetic loci influencing the recovery process using accurate phenotyping to produce the largest GWAS (genome-wide association study) in ischemic stroke recovery to date. METHODS AND RESULTS: A 12-cohort, 2-phase (discovery-replication and joint) meta-analysis of GWAS included anterior-territory and previously independent ischemic stroke cases. Functional outcome was recorded using 3-month modified Rankin Scale. Analyses were adjusted for confounders such as discharge National Institutes of Health Stroke Scale. A gene-based burden test was performed. The discovery phase (n=1225) was followed by open (n=2482) and stringent joint-analyses (n=1791). Those cohorts with modified Rankin Scale recorded at time points other than 3-month or incomplete data on previous functional status were excluded in the stringent analyses. Novel variants in PATJ (Pals1-associated tight junction) gene were associated with worse functional outcome at 3-month after stroke. The top variant was rs76221407 (G allele, β=0.40, P=1.70×10-9). CONCLUSIONS: Our results identify a set of common variants in PATJ gene associated with 3-month functional outcome at genome-wide significance level. Future studies should examine the role of PATJ in stroke recovery and consider stringent phenotyping to enrich the information captured to unveil additional stroke outcome loci

Structure and biological activity of gonadotropin-releasing hormone isoforms isolated from rat and hamster brains

Rat and hamster brain tissues were used to investigate the possible existence of a follicle stimulating hormone (FSH)-releasing factor with similar characteristics to the lamprey gonadotropin-releasing hormone III (lGnRH-III) form proposed in previous reports. The present studies involved isolation and purification of the molecule by high-performance liquid chromatography (HPLC), identification by radioimmunoassay, sequence analysis by automated Edman degradation, mass spectrometry and examination of biological activity. Hypothalamic extracts from both species contained an HPLC fraction that was immunoreactive to GnRH and coeluted with lGnRH-III and 9-hydroxyproline mGnRH ([Hyp(9)]GnRH). Determination of primary structure from purified total brain material demonstrated that the isolated molecule was [Hyp(9)]GnRH. This is the first report showing the presence of the posttranslationally modified form already known as [Hyp(9)]GnRH by primary sequence analysis. The biological activity of distinct GnRH peptides was also tested in vitro for gonadotropin release using rat pituitary primary cell cultures. The results showed that [Hyp(9)]GnRH stimulated both luteinizing hormone and FSH release, as already reported, whereas lGnRH-III had no action on the secretion of either gonadotropin.Fil: Montaner, Alejandro Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Ciencia y Tecnología ; ArgentinaFil: Mongiat, Lucas Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Lux, Victoria Adela R.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Park, M. K.. The Salk Institute; Estados UnidosFil: Fischer, W. H.. The Salk Institute; Estados UnidosFil: Rivier, J. E.. The Salk Institute; Estados UnidosFil: Lescheid, D.. University Of Victoria; Canadá. University of Toronto; CanadáFil: Lovejoy, D.. University of Toronto; CanadáFil: Libertun, Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Sherwood, N. M.. University Of Victoria; Canadá. University of Toronto; CanadáFil: Somoza, Gustavo Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Ciencia y Tecnología ; Argentin