From types to sets by local type definitions in higher-order logic

Types in Higher-Order Logic (HOL) are naturally interpreted as nonempty sets—this intuition is reflected in the type definition rule for the HOL-based systems (including Isabelle/HOL), where a new type can be defined whenever a nonempty set is exhibited. However, in HOL this definition mechanism cannot be applied inside proof contexts. We propose a more expressive type definition rule that addresses the limitation and we prove its soundness. This higher expressive power opens the opportunity for a HOL tool that relativizes type-based statements to more flexible set-based variants in a principled way. We also address particularities of Isabelle/HOL and show how to perform the relativization in the presence of type classes

Peripheral blood mononuclear cells (PBMC) microbiome is not affected by colon microbiota in healthy goats

This work was supported by grants from the Spanish Ministry of Science and Innovation (MCI) co-financed with FEDER funds [AGL2017-86757 to LA, AGL2017-86938-R to DRY]. Other contributions were SAF2015-65327-R to JA and SAF2015-73549-JIN to HR. LA is a Ramón y Cajal fellow [RYC-2013-13666] from the Spanish Ministry of Science and Innovation. APC is a recipient of a fellowship from the University of the Basque Country. We thank the MCI for the Severo Ochoa Excellence accreditation (SEV-2016-0644) and the Basque Department of Industry, Tourism and Trade (Etortek and Elkartek programs

miRanalyzer: an update on the detection and analysis of microRNAs in high-throughput sequencing experiments

We present a new version of miRanalyzer, a web server and stand-alone tool for the detection of known and prediction of new microRNAs in high-throughput sequencing experiments. The new version has been notably improved regarding speed, scope and available features. Alignments are now based on the ultrafast short-read aligner Bowtie (granting also colour space support, allowing mismatches and improving speed) and 31 genomes, including 6 plant genomes, can now be analysed (previous version contained only 7). Differences between plant and animal microRNAs have been taken into account for the prediction models and differential expression of both, known and predicted microRNAs, between two conditions can be calculated. Additionally, consensus sequences of predicted mature and precursor microRNAs can be obtained from multiple samples, which increases the reliability of the predicted microRNAs. Finally, a stand-alone version of the miRanalyzer that is based on a local and easily customized database is also available; this allows the user to have more control on certain parameters as well as to use specific data such as unpublished assemblies or other libraries that are not available in the web server. miRanalyzer is available at http://bioinfo2.ugr.es/miRanalyzer/miRanalyzer.php.The Ministry of Innovation and Science of the Spanish Government (BIO2010-20219 to M.H.); the Junta de Andalucia (P07FQM3163 to M.H.); the ‘Juan de la Cierva’ fellowship (to M.H.); the Department of Industry, Tourism and Trade of the Government of the Autonomous Community of the Basque Country (Etortek Research Programs 2009/20011 to A.M.A.); from the Innovation Technology Department of the Bizkaia County (to A.M.A.). Funding for open access charge: Department of Industry, Tourism and Trade of the Government of the Autonomous Community of the Basque Country (Etortek Research Programs 2009/2011 to A.M.A.)

Generation, establishment and characterization of a pluripotent stem cell line (CVTTHi001-A) from primary fibroblasts isolated from a patient with activated PI3 kinase delta syndrome (APDS2)

APDS2 is caused by mutations in PIK3R1 gene resulting in constitutive PI3Kδ activation. PI3Kδ is predominantly expressed in leukocytes and plays critical roles in regulating immune responses. Here we first derived fibroblast primary cells from a skin biopsy of a patient carrying a heterozygous single T deletion in intron 11 of the PIK3R1 gene. We next present the derivation of an induced pluripotent stem cell (iPS) line using a non-integrative reprogramming technology. Pluripotent-related hallmarks are further shown, including: iPSCs self-renewal and expression of pluripotent and differentiation markers after in vitro differentiation towards embryonic germ layers, assessed by RT-PCR and immunofluorescence

N7-methylguanosine methylation of tRNAs regulates survival to stress in cancer

Tumour progression and therapy tolerance are highly regulated and complex processes largely dependent on the plasticity of cancer cells and their capacity to respond to stress. The higher plasticity of cancer cells highlights the need for identifying targetable molecular pathways that challenge cancer cell survival. Here, we show that

Non‑invasive prostate cancer detection by measuring miRNA variants (isomiRs) in urine extracellular vesicles

The authors thank J. Bossenga for collecting urine and P.P. Eijk for their technical assistance in smallRNA sequencing library preparations.In many cancer types, the expression and function of ~22 nucleotide‑long microRNAs (miRNA) is deregulated. Mature miRNAs can be stably detected in extracellular vesicles (EVs) in biofluids, therefore they are considered to have great potential as biomarkers. In the present study, we investigated whether miRNAs have a distinct expression pattern in urine‑EVs of prostate cancer (PCa) patients compared to control males. By next generation sequencing, we determined the miRNA expression in a discovery cohort of 4 control men and 9 PCa patients. miRNAs were validated by using a stemloop RT‑PCR in an independent cohort of 74 patients (26 control and 48 PCa‑patients). Whereas standard mapping protocols identified > 10 PCa associated miRNAs in urinary EVs, miR‑21, miR‑375 and miR‑204 failed to robustly discriminate for disease in a validation study with RT‑PCR‑detection of mature miRNA sequences. In contrast, we observed that miRNA isoforms (isomiRs) with 3′ end modifications were highly discriminatory between samples from control men and PCa patients. Highly differentially expressed isomiRs of miR‑21, miR‑204 and miR‑375 were subsequently validated in an independent group of 74 patients. Receiver‑operating characteristic analysis was performed to evaluate the diagnostic performance of three isomiRs, resulting in a 72.9% sensitivity with a high (88%) specificity and an area under the curve (AUC) of 0.866. In comparison, prostate specific antigen had an AUC of 0.707 and measuring the mature form of these miRNAs yielded a lower 70.8% sensitivity and 72% specificity (AUC 0.766). We propose that isomiRs may carry discriminatory information which is useful to generate stronger biomarkers.Stichting Urologie 1973VUmc-CCAWorldwide Cancer Research (AICR) 15-1005KWF-VU-5510Worldwide Cancer Research 15-100

TRIB3 suppresses tumorigenesis by controlling mTORC2/AKT/FOXO signaling.

In a recent article, we found that Tribbles pseudokinase 3 (TRIB3) plays a tumor suppressor role and that this effect relies on the dysregulation of the phosphorylation of v-akt murine thymoma viral oncogene homolog (AKT) by the mammalian target of rapamycin complex 2 (mTORC2 complex), and the subsequent hyperphosphorylation and inactivation of the transcription factor Forkhead box O3 (FOXO3)

Extracellular Vesicles From Liver Progenitor Cells Downregulates Fibroblast Metabolic Activity and Increase the Expression of Immune-Response Related Molecules

Extracellular vesicles (EVs) mediate cell-to-cell crosstalk whose content can induce changes in acceptor cells and their microenvironment. MLP29 cells are mouse liver progenitor cells that release EVs loaded with signaling cues that could affect cell fate. In the current work, we incubated 3T3-L1 mouse fibroblasts with MLP29-derived EVs, and then analyzed changes by proteomics and transcriptomics. Results showed a general downregulation of protein and transcript expression related to proliferative and metabolic routes dependent on TGF-beta. We also observed an increase in the ERBB2 interacting protein (ERBIN) and Cxcl2, together with an induction of ribosome biogenesis and interferon-related response molecules, suggesting the activation of immune system signaling

HuR/ELAVL1 drives malignant peripheral nerve sheath tumor growth and metastasis

Cancer cells can develop a strong addiction to discrete molecular regulators, which control the aberrant gene expression programs that drive and maintain the cancer phenotype. Here, we report the identification of the RNA-binding protein HuR/ELAVL1 as a central oncogenic driver for malignant peripheral nerve sheath tumors (MPNSTs), which are highly aggressive sarcomas that originate from cells of the Schwann cell lineage. HuR was found to be highly elevated and bound to a multitude of cancer-associated transcripts in human MPNST samples. Accordingly, genetic and pharmacological inhibition of HuR had potent cytostatic and cytotoxic effects on tumor growth, and strongly suppressed metastatic capacity in vivo. Importantly, we linked the profound tumorigenic function of HuR to its ability to simultaneously regulate multiple essential oncogenic pathways in MPNST cells, including the Wnt/β-catenin, YAP/TAZ, RB/E2F, and BET pathways, which converge on key transcriptional networks. Given the exceptional dependency of MPNST cells on HuR for survival, proliferation, and dissemination, we propose that HuR represents a promising therapeutic target for MPNST treatment

Microbioma de las células mononucleares de sangre periférica en cabras

1 página.- Trabajo presentado a las: XIX Jornadas sobre Producción Animal AIDA. On line. Zaragoza, España, 1-2 junio 2021.Financiado por los proyectos AGL2017-86757 y AGL2017-86938-R