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Different regions of RNA molecules can often engage in specific interactions with distinct RNA-binding proteins (RBPs), giving rise to diverse modalities of RNA regulation and function. However, there are currently no methods for unbiased identification of RBPs that interact with specific RNA regions in living cells and under endogenous settings. Here we introduce TREX (targeted RNase H-mediated extraction of crosslinked RBPs)-a highly sensitive approach for identifying proteins that directly bind to specific RNA regions in living cells. We demonstrate that TREX outperforms existing methods in identifying known interactors of U1 snRNA, and reveals endogenous region-specific interactors of NORAD long noncoding RNA. Using TREX, we generated a comprehensive region-by-region interactome for 45S rRNA, uncovering both established and previously unknown interactions that regulate ribosome biogenesis. With its applicability to different cell types, TREX is an RNA-centric tool for unbiased positional mapping of endogenous RNA-protein interactions in living cells., (© 2024. The Author(s).)

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., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)

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 m 6 A 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., (© 2021. The Author(s).)

Introduction: Over the last two decades, the outcomes of patients with multiple myeloma (MM), a malignant plasma cells dyscrasia, have dramatically improved. The development and the introduction of the immunomodulatory drugs (IMiDs) which include thalidomide, lenalidomide, and pomalidomide, have contributed significantly to these improvements., Evidence Acquisition: The IMiDs have been shown a multitude of mechanisms of action, including antiangiogenic, cytotoxic and immunomodulatory. The more recent discoveries that the IMiDs bind to cereblon and thus regulate the ubiquitination of key transcription factors including IKZF1 and IKZF3, have provided new insight about their activities., Evidence Synthesis: The IMIDs are widely used in the treatment of the different setting of MM patients and particularly lenalidomide represents the backbone in the therapy of newly diagnosed transplant eligible and transplant ineligible patients, in the maintenance setting post-transplant and in the relapsed/refractory setting, while pomalidomide is currently utilized in the relapsed/refractory setting., Conclusions: Here the mechanisms of action, the clinical efficacy and the management of side effects are reviewed as well as the new classes of cereblon E3 ligase modulator (CELMoD) and their promising clinical data are described.

The Multiple Myeloma (MM) is a plasma cells hematological malignancy with a median age of 69 years at diagnosis. The autologous stem cell transplantation is the standard of care for this disease but less than half of newly diagnosed patients are assessed for this treatment due to comorbidities or complications of disease. The management of transplant ineligible MM patients is based on the balance safety and efficacy of the new available regimen and a careful assessment of the frailty status is mandatory to define the goals. In this review we discuss of the clinical dilemmas in the management and define how to manage them based on the evidence from clinical trials and "real life" experience., Competing Interests: Conflict of interest: The authors declare no potential conflict of interest., (©Copyright: the Author(s).)

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

Background: The 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 Review: Along 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.

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.

This article presents a description of the design, development, and implementation of web-based software and dedicated hardware which allows for the remote monitoring and control of a drip irrigation system. The hardware consists of in-field stations which are strategically distributed in the field and equipped with different sensors and communication devices; a weather station and drip irrigation system complete the setup. The web-based software makes it possible to remotely access and process the information gathered by all the stations and the irrigation controller. The proposed system was implemented in a young olive orchard, located in the province of San Juan, an arid region of Argentina. The system was installed and evaluated during the seasons 2014⁻2015 and 2015⁻2016. Four regulated irrigation strategies were proposed in the olive orchard to test its behavior. In this pilot experiment, the precision irrigation system was a useful tool for precisely managing the irrigation process, applying only the required amount of water (precise irrigation). Regulated deficit irrigation experiments, on the other hand, have demonstrated the sensitivity of olives to water restriction. The precision irrigation system made it possible to control soil moisture levels, avoiding water stress in the control treatment.

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 O(2), hardness, alkalinity, chemical oxygen demand, total suspended solids, ionic species (NH(4)(+), NO(3)(-), NO(2)(-), PO(4)(3-), SO(4)(2-), Cl(-), F(-)), elements (Cr(III), Cr(VI), 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.

Following the recent discussion on the puzzling nature of the interactions in the nanotubular system Na(2)V(3)O(7), we present a detailed ab initio microscopic analysis of its electronic and magnetic properties. By means of a nontrivial downfolding study we propose an effective model in terms of tubes of nine-site rings with the geometry of a spin-diamond necklace with frustrated inter-ring interactions. We show that this model provides a quantitative account of the observed magnetic behavior.