DIS3L2: Unveiling a New Player in Tumorigenesis, with a Key Role in Colorectal Cancer

DIS3L2 is a 3’-5’ exoribonuclease that recognizes and degrades uridylated transcripts in an exosome-independent manner and participates in several RNA degradation pathways, such as the nonsense-mediated mRNA decay, or the surveillance of aberrant structured non-coding RNAs. Although some studies have linked DIS3L2 to tumorigenesis and cancer-related processes, its exact role in the development and progression of cancer has remained unclear since the discovery of DIS3L2's ribonuclease activity a decade ago. While some authors have reported evidence of a tumor suppressor role for this exoribonuclease, other studies have shown DIS3L2 as a driver of tumorigenesis. Although differences in tissue type and methodologic approaches may somewhat account for the opposing findings, a recent study from our group further supports a pro-tumorigenic role for DIS3L2, this time in promoting colorectal cancer (CRC) progression. Indeed, proper DIS3L2 expression was proven essential to maintain key tumorigenic properties in CRC cells, including cell proliferation and invasion. Here, we summarize the current state of knowledge regarding the impact of DIS3L2 in cancer, namely in colorectal cancer. The collected data unveils DIS3L2 as a novel putative therapeutic target in cancer that warrants further investigation.This work was supported by Instituto Nacional de Saúde Doutor Ricardo Jorge and Fundação para a Ciência e a Tecnologia (FCT) [UID/MULTI/04046/2019 Research Unit Grant (to BioISI)]. Juan F. García-Moreno was recipient of a fellowship from BioSys PhD programme (PD/BD/142898/2018)info:eu-repo/semantics/publishedVersio

Nonsense-mediated RNA decay and its bipolar function in cancer

ReviewNonsense-mediated decay (NMD) was first described as a quality-control mechanism that targets and rapidly degrades aberrant mRNAs carrying premature termination codons (PTCs). However, it was found that NMD also degrades a significant number of normal transcripts, thus arising as a mechanism of gene expression regulation. Based on these important functions, NMD regulates several biological processes and is involved in the pathophysiology of a plethora of human genetic diseases, including cancer. The present review aims to discuss the paradoxical, pro- and anti-tumorigenic roles of NMD, and how cancer cells have exploited both functions to potentiate the disease. Considering recent genetic and bioinformatic studies, we also provide a comprehensive overview of the present knowledge of the advantages and disadvantages of different NMD modulation-based approaches in cancer therapy, reflecting on the challenges imposed by the complexity of this disease. Furthermore, we discuss significant advances in the recent years providing new perspectives on the implications of aberrant NMD-escaping frameshifted transcripts in personalized immunotherapy design and predictive biomarker optimization. A better understanding of how NMD differentially impacts tumor cells according to their own genetic identity will certainly allow for the application of novel and more effective personalized treatments in the near future.Gonçalo Nogueira, Rafael Fernandes, and Juan Fernandez García-Moreno are recipients of a fellowship from BioSys PhD programme PD65-2012 (SFRH/PD/BD/130959/2017, SFRH/BD/114392/2016 and SFRH/PD/BD/142898/2018, respectively) from FCT. This work was partially supported by UID/MULTI/04046/2019 Research Unit grant (to BioISI).info:eu-repo/semantics/publishedVersio

Some asymptotics for Sobolev orthogonal polynomials involving Gegenbauer weights

AbstractWe consider the Sobolev inner product 〈f,g〉=∫−11f(x)g(x)(1−x2)α−12dx+∫f′(x)g′(x)dψ(x),α>−12, where dψ is a measure involving a Gegenbauer weight and with mass points outside the interval (−1,1). We study the asymptotic behaviour of the polynomials which are orthogonal with respect to this inner product. We obtain the asymptotics of the largest zeros of these polynomials via a Mehler–Heine type formula. These results are illustrated with some numerical experiments

Traffic Optimization Through Waiting Prediction and Evolutive Algorithms

Traffic optimization systems require optimization procedures to optimize traffic light timing settings in order to improve pedestrian and vehicle mobility. Traffic simulators allow obtaining accurate estimates of traffic behavior by applying different timing configurations, but require considerable computational time to perform validation tests. For this reason, this project proposes the development of traffic optimizations based on the estimation of vehicle waiting times through the use of different prediction techniques and the use of this estimation to subsequently apply evolutionary algorithms that allow the optimizations to be carried out. The combination of these two techniques leads to a considerable reduction in calculation time, which makes it possible to apply this system at runtime. The tests have been carried out on a real traffic junction on which different traffic volumes have been applied to analyze the performance of the system

Asymptotics for Jacobi–Sobolev orthogonal polynomials associated with non-coherent pairs of measures

AbstractWe consider the Sobolev inner product 〈f,g〉=∫−11f(x)g(x)dψ(α,β)(x)+∫f′(x)g′(x)dψ(x), where dψ(α,β)(x)=(1−x)α(1+x)βdx with α,β>−1, and ψ is a measure involving a rational modification of a Jacobi weight and with a mass point outside the interval (−1,1). We study the asymptotic behaviour of the polynomials which are orthogonal with respect to this inner product on different regions of the complex plane. In fact, we obtain the outer and inner strong asymptotics for these polynomials as well as the Mehler–Heine asymptotics which allow us to obtain the asymptotics of the largest zeros of these polynomials. We also show that in a certain sense the above inner product is also equilibrated

Intra-tumor heterogeneity in TP53 null high grade serous ovarian carcinoma progression

[Background]: High grade serous ovarian cancer is characterised by high initial response to chemotherapy but poor outcome in the long term due to acquired resistance. One of the main genetic features of this disease is TP53 mutation. The majority of TP53 mutated tumors harbor missense mutations in this gene, correlated with p53 accumulation. TP53 null tumors constitute a specific subgroup characterised by nonsense, frameshift or splice-site mutations associated to complete absence of p53 expression. Different studies show that this kind of tumors may have a worse prognosis than other TP53 mutated HGSC. [Methods]: In this study, we sought to characterise the intra-tumor heterogeneity of a TP53 null HGSC consisting of six primary tumor samples, two intra-pelvic and four extra-pelvic recurrences using exome sequencing and comparative genome hybridisation. [Results]: Significant heterogeneity was found among the different tumor samples, both at the mutational and copy number levels. Exome sequencing identified 102 variants, of which only 42 were common to all three samples; whereas 7 of the 18 copy number changes found by CGH analysis were presented in all samples. Sanger validation of 20 variants found by exome sequencing in additional regions of the primary tumor and the recurrence allowed us to establish a sequence of the tumor clonal evolution, identifying those populations that most likely gave rise to recurrences and genes potentially involved in this process, like GPNMB and TFDP1. Using functional annotation and network analysis, we identified those biological functions most significantly altered in this tumor. Remarkably, unexpected functions such as microtubule-based movement and lipid metabolism emerged as important for tumor development and progression, suggesting its potential interest as therapeutic targets. [Conclusions]: Altogether, our results shed light on the clonal evolution of the distinct tumor regions identifying the most aggressive subpopulations and at least some of the genes that may be implicated in its progression and recurrence, and highlights the importance of considering intra-tumor heterogeneity when carrying out genetic and genomic studies, especially when these are aimed to diagnostic procedures or to uncover possible therapeutic strategies.This work has been supported by grants from the AECC network-2012, Telemarató 2013, Instituto de Salud Carlos III (ISCIII) (PI13/00132 and RETIC-RD12/0036/0007), GEIS award 2013, and by the Community of Madrid (S2010/BMD-2303). AM is a predoctoral student supported by FPU fellowship (Spanish Education Ministry). PGS is founded by postdoc contracts from the AECC Scientific Foundation.Peer Reviewe

RepA-WH1 prionoid: Clues from bacteria on factors governing phase transitions in amyloidogenesis

10 p.-1 fig.In bacterial plasmids, Rep proteins initiate DNA replication by undergoing a structural transformation coupled to dimer dissociation. Amyloidogenesis of the ‘winged-helix’ N-terminal domain of RepA (WH1) is triggered in vitro upon binding to plasmid-specific DNA sequences, and occurs at the bacterial nucleoid in vivo. Amyloid fibers are made of distorted RepA-WH1 monomers that assemble as single or double intertwined tubular protofilaments. RepA-WH1 causes in E. coli an amyloid proteinopathy, which is transmissible from mother to daughter cells, but not infectious, and enables conformational imprinting in vitro and in vivo; i.e. RepA-WH1 is a ‘prionoid’. Microfluidics allow the assessment of the intracellular dynamics of RepA-WH1: bacterial lineages maintain two types (strains-like) of RepA-WH1 amyloids, either multiple compact cytotoxic particles or a single aggregate with the appearance of a fluidized hydrogel that it is mildly detrimental to growth. The Hsp70 chaperone DnaK governs the phase transition between both types of RepA-WH1 aggregates in vivo, thus modulating the vertical propagation of the prionoid. Engineering chimeras between the Sup35p/[PSI*] prion and RepA-WH1 generates [REP-PSI*], a synthetic prion exhibiting strong and weak phenotypic variants in yeast. These recent findings on a synthetic, self-contained bacterial prionoid illuminate central issues of protein amyloidogenesis.Research on RepA-WH1 amyloids at CIBCSIC is currently financed by Spanish MINECO grants BIO2012-30852 and CSD2009-00088.Peer reviewe

Direct analysis of olive oil and other vegetable oils by mass spectrometry: a review

Virgin olive oil (VOO) is a highly valued vegetable oil often subjected to fraud practices such as adulteration with lower prized oils such as seed oils and refined olive oil. Thus, there is a need to provide rapid tools that allow high-throughput authentication and quality control of VOO as well as other valued oils. Mass spectrometry offers unique features -such as specificity, sensitivity and speed of analysis-that map well against this challenge, either those based on atmospheric pressure ionization methods (ESI and APCI) or those occurring under vacuum conditions such as MALDI for nonvolatile species or headspace sampling-mass spectrometry using electron impact ionization (HS-MS) or chemical ionization (proton transfer reaction mass spectrometry (PTR-MS) and selected ion flow tube mass spectrometry (SIFT-MS)) for volatile fraction analysis. In addition, more recent atmospheric pressure methods (Ambient MS) enable direct analysis with minor or even no sample manipulation. The aim of this article is to provide a critical overview on all these methods and their potential use for vegetable oil characterization, highlighting the strengths and weaknesses of the differentMarie Sklodowska-Curie (MSCA) grant agreement number 840743, EU FEDER funds and the Research Programme of the University of Jaen (Plan 2019–2020, Research programme “Acción 10”) and Regional Government of Andalucía, Spain (Project Ref. PY2018-1211)