An ERK1/2-driven RNA-binding switch in nucleolin drives ribosome biogenesis and pancreatic tumorigenesis downstream of RAS oncogene

Oncogenic RAS signaling reprograms gene expression through both transcriptional and post-transcriptional mechanisms. While transcriptional regulation downstream of RAS is relatively well characterized, how RAS post-transcriptionally modulates gene expression to promote malignancy remains largely unclear. Using quantitative RNA interactome capture analysis, we here reveal that oncogenic RAS signaling reshapes the RNA-bound proteomic landscape of pancreatic cancer cells, with a network of nuclear proteins centered around nucleolin displaying enhanced RNA-binding activity. We show that nucleolin is phosphorylated downstream of RAS, which increases its binding to pre-ribosomal RNA (rRNA), boosts rRNA production, and promotes ribosome biogenesis. This nucleolin-dependent enhancement of ribosome biogenesis is crucial for RAS-induced pancreatic cancer cell proliferation and can be targeted therapeutically to inhibit tumor growth. Our results reveal that oncogenic RAS signaling drives ribosome biogenesis by regulating the RNA-binding activity of nucleolin and highlight a crucial role for this mechanism in RAS-mediated tumorigenesis

Chemical analyses of spring waters and factor analysis to monitor the functioning of a karstic system. The role of precipitations regimen and anthropic pressures

An approach is presented to study the functioning of a karstic massif and assess the adverse effects of the anthropogenic pressure by monitoring some water chemical and physical parameters of its main springs. The approach has been applied to the Sette Comuni Plateau (Veneto Region, Italy) hosting a well developed karstic system, whose aquifer presents high vulnerability and undergoes a relevant anthropogenic pressure. The Oliero springs, amongst the largest karstic springs in Europe, are the main water output of the plateau. Electrical conductivity, pH, dissolved O2, hardness, alkalinity, chemical oxygen demand, total suspended solids, ionic species (NH4+, NO3−, NO2−, PO43−, SO42−, Cl−, F−), elements (CrIII, CrVI, Mn, Fe, Ni, Cu, Zn, As, Cd, Hg, Pb), and some chlorinated solvents were monitored for one year. This study presents the application of a factor analysis on the water parameters enabling the identification of the dominant chemical and biological processes and pollution sources affecting the karstic system. Results show four factors which are interpreted as karstification, photosynthesis, storm flow pollution and anions. Finally, by associating metals, chemical oxygen demand and total suspended solids with the amount of rainfall in the 48 h before samplings, further detailed information to the fast response of the aquifer to precipitation events was detected and interpreted according to the factor analysis results. The proposed approach, by providing information on the functioning of the aquifer, may help the management of the karstic plateau and is easily adaptable to similar environments

RNA modifications detection by comparative Nanopore direct RNA sequencing.

RNA molecules undergo a vast array of chemical post-transcriptional modifications (PTMs) that can affect their structure and interaction properties. In recent years, a growing number of PTMs have been successfully mapped to the transcriptome using experimental approaches relying on high-throughput sequencing. Oxford Nanopore direct-RNA sequencing has been shown to be sensitive to RNA modifications. We developed and validated Nanocompore, a robust analytical framework that identifies modifications from these data. Our strategy compares an RNA sample of interest against a non-modified control sample, not requiring a training set and allowing the use of replicates. We show that Nanocompore can detect different RNA modifications with position accuracy in vitro, and we apply it to profile m6A in vivo in yeast and human RNAs, as well as in targeted non-coding RNAs. We confirm our results with orthogonal methods and provide novel insights on the co-occurrence of multiple modified residues on individual RNA molecules.The Kouzarides laboratory is supported by Cancer Research UK (grant reference RG72100) and core support from the Wellcome Trust (core grant reference WT203144) and Cancer Research UK (grant reference C6946/A24843). PPA was supported by a Borysiewicz Biomedical Sciences postdoctoral fellowship (University of Cambridge) and AL by a COFUND Marie Skłodowska-Curie Actions postdoctoral fellowship (EMBL). FW and TS are supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001203), the UK Medical Research Council (FC001203), and the Wellcome Trust (FC001203). IB and V Miano are supported by Cancer Research UK (grant reference RG86786) and by the Joseph Mitchell Fund

Correction to: Relevance of biomarkers across different neurodegenerative diseases

An amendment to this paper has been published and can be accessed via the original article

Correction to: Relevance of biomarkers across different neurodegenerative diseases.

An amendment to this paper has been published and can be accessed via the original article

The spread of COVID-19 in six western metropolitan regions:a false myth on the excess of mortality in Lombardy and the defense of the city of Milan

We analyzed the spread of the COVID-19 epidemic in 6 metropolitan regions with similar demographic characteristics, daytime commuting population and business activities: the New York metropolitan area, the Île-de-France region, the Greater London county, Bruxelles-Capital, the Community of Madrid and the Lombardy region. The highest mortality rates 30-days after the onset of the epidemic were recorded in New York (81.2 x 100,000) and Madrid (77.1 x 100,000). Lombardy mortality rate is below average (41.4 per 100,000), and it is the only situation in which the capital of the region (Milan) has not been heavily impacted by the epidemic wave. Our study analyzed the role played by containment measures and the positive contribution offered by the hospital care system. (www.actabiomedica.it)

Perspectives in fluid biomarkers in neurodegeneration from the 2019 biomarkers in neurodegenerative diseases course - A joint PhD student course at University College London and University of Gothenburg

Until relatively recently, a diagnosis of probable Alzheimer's disease (AD) and other neurodegenerative disorders was principally based on clinical presentation, with post-mortem examination remaining a gold standard for disease confirmation. This is in sharp contrast to other areas of medicine, where fluid biomarkers, such as troponin levels in myocardial infarction, form an integral part of the diagnostic and treatment criteria. There is a pressing need for such quantifiable and easily accessible tools in neurodegenerative diseases. In this paper, based on lectures given at the 2019 Biomarkers in Neurodegenerative Diseases Course, we provide an overview of a range of cerebrospinal fluid (CSF) and blood biomarkers in neurodegenerative disorders, including the 'core' AD biomarkers amyloid β (Aβ) and tau, as well as other disease-specific and general markers of neuroaxonal injury. We then highlight the main challenges in the field, and how those could be overcome with the aid of new methodological advances, such as assay automation, mass spectrometry and ultrasensitive immunoassays. As we hopefully move towards an era of disease-modifying treatments, reliable biomarkers will be essential to increase diagnostic accuracy, allow for earlier diagnosis, better participant selection and disease activity and treatment effect monitoring

Relevance of biomarkers across different neurodegenerative diseases.

BackgroundThe panel of fluid- and imaging-based biomarkers available for neurodegenerative disease research is growing and has the potential to close important gaps in research and the clinic. With this growth and increasing use, appropriate implementation and interpretation are paramount. Various biomarkers feature nuanced differences in strengths, limitations, and biases that must be considered when investigating disease etiology and clinical utility. For example, neuropathological investigations of Alzheimer's disease pathogenesis can fall in disagreement with conclusions reached by biomarker-based investigations. Considering the varied strengths, limitations, and biases of different research methodologies and approaches may help harmonize disciplines within the neurodegenerative disease field.Purpose of reviewAlong with separate review articles covering fluid and imaging biomarkers in this issue of Alzheimer's Research and Therapy, we present the result of a discussion from the 2019 Biomarkers in Neurodegenerative Diseases course at the University College London. Here, we discuss themes of biomarker use in neurodegenerative disease research, commenting on appropriate use, interpretation, and considerations for implementation across different neurodegenerative diseases. We also draw attention to areas where biomarker use can be combined with other disciplines to understand issues of pathophysiology and etiology underlying dementia. Lastly, we highlight novel modalities that have been proposed in the landscape of neurodegenerative disease research and care