Exploring functional conservation in silico: a new machine learning approach to RNA-editing.

Around 50 years ago, molecular biology opened the path to understand changes in forms, adaptations, complexity, or the basis of human diseases through myriads of reports on gene birth, gene duplication, gene expression regulation, and splicing regulation, among other relevant mechanisms behind gene function. Here, with the advent of big data and artificial intelligence (AI), we focus on an elusive and intriguing mechanism of gene function regulation, RNA editing, in which a single nucleotide from an RNA molecule is changed, with a remarkable impact in the increase of the complexity of the transcriptome and proteome. We present a new generation approach to assess the functional conservation of the RNA-editing targeting mechanism using two AI learning algorithms, random forest (RF) and bidirectional long short-term memory (biLSTM) neural networks with an attention layer. These algorithms, combined with RNA-editing data coming from databases and variant calling from same-individual RNA and DNA-seq experiments from different species, allowed us to predict RNA-editing events using both primary sequence and secondary structure. Then, we devised a method for assessing conservation or divergence in the molecular mechanisms of editing completely in silico: the cross-testing analysis. This novel method not only helps to understand the conservation of the editing mechanism through evolution but could set the basis for achieving a better understanding of the adenosine-targeting mechanism in other fields.

Regional Workshop on Optimization of Protection in Pediatric Interventional Radiology in Latin American and Caribbean Countries.

ABSTRACT: The purpose of this article is to describe the activities developed within the framework "Regional Workshop on Optimization of Protection in Pediatric Interventional Radiology in Latin American and Caribbean countries," developed between October 16th and 19th of the year 2023 in the city of San José, Costa Rica. The workshop was carried out as part of a joint work between the Pan American Health Organization (PAHO) and the World Health Organization (WHO), in cooperation with the International Atomic Energy Agency (IAEA). The main objective of the regional workshop was to gather the experiences and future work planning among participants in the Optimization of Protection in Pediatric Interventional Radiology in Latin America and the Caribbean (OPRIPALC) program. It involved professionals from 14 centers across 11 countries in the region, along with 4 experts from PAHO/WHO/IAEA. The work modalities during the workshop consisted of keynote presentations, individual presentations, group work, and general discussions. An online survey was carried out after the workshop, with the objective of knowing the opinion of the event participants and determining the impact and projection of the OPRIPALC program. During the workshop the centers had to present their experiences: the use of the DOLQA dose management system was presented and work was done on the consensus document on good practices. The activities, topics and organization of the workshop were valued positively by the participants. There is unanimity among the centers that the OPRIPALC program has had a positive impact and they wish to continue actively participating in the next biennium.

Medical staff dose estimation during pediatric cardiac interventional procedures.

The purpose of this study is to evaluate the occupational doses (eye lens, extremities and whole body) in paediatric cardiac interventional and diagnostic catheterization procedures performed in a paediatric reference hospital located in Recife, Pernambuco. For eye lens dosimetry, the results show that the left eye receives a higher dose than the right eye, and there is a small difference between the doses received during diagnostic (D) and therapeutic (T) procedures. The extrapolated annual values for the most exposed eye are close to the annual limit. For doses to the hands, it was observed that in a significant number of procedures (37 out of 45 therapeutic procedures, or 82%) at least one hand of the physician was exposed to the primary beam. During diagnostic procedures, the physician's hand was in the radiation field in 11 of the 17 catheterization procedures (65%). This resulted in a 10-fold increase in dose to the hands. The results underscore the need for optimization of radiation safety and continued efforts to engage staff in a radiation safety culture.

Optimization of Radiation Protection in Pediatric Interventional Radiology in Latin America and the Caribbean: Development, Advancements, Challenges and Achievements of the OPRIPALC Program.

This article presents the development, advancements, challenges and achievements of the "Optimization of Protection in Pediatric Interventional Radiology in Latin America and the Caribbean" (OPRIPALC) program. This international initiative is led by the World Health Organization, the Pan American Health Organization and the International Atomic Energy Agency. The main objectives of OPRIPALC are to foster a culture of radiological protection in pediatric interventions, enhance these procedures' quality, and define optimization strategies such as the use of diagnostic reference levels (DRLs). Currently, 33 centers from 12 countries participate actively in the program. Significant progress has been made towards the proposed objectives, overcoming the challenges posed by the COVID-19 pandemic. Through many virtual meetings for coordination, planning, training and follow-up, a comprehensive set of DRLs for both diagnostic and therapeutic procedures, categorized by weight and age, have been established and are in use. A consensus document on good practices is in the final stage of development. The program's continuation into at least a second phase is essential to address pending issues, including the integration of automatic dose management systems, the levels of occupational radiation doses, their correlation with pediatric patient doses, and strategies to reduce them.

Local Diagnostic Reference Levels for Pediatric Interventional Cardiology Procedures in Argentina.

The aim of this work was to propose a preliminary local diagnostic reference levels (DRL) for pediatric interventional cardiology (PIC) procedures in Argentina, for different ranges of age and weight. This work has been conducted in the framework of the "Optimization of Protection in Pediatric Interventional Radiology in Latin America and the Caribbean" (OPRIPALC) program coordinated by the World Health Organization and the Pan American Health Organization in cooperation with the International Atomic Energy Agency to ensuring that radiation exposures of pediatric patients are the minimum necessary during fluoroscopy-guided interventional procedures. The local DRL values presented in this paper by weight group and age group were 7.1 Gy·cm2 (<5 kg), 10.7 Gy·cm2 (5-15 kg), 18.0 Gy·cm2 (15-30 kg), 15.9 Gy·cm2 (30-50 kg), and 28.2 Gy·cm2 (50-80 kg) and 5.3 Gy·cm2 (<1), 11.2 Gy·cm2 (1 to 5<), 19.6 Gy·cm2 (5 to 10<), and 21.4 Gy·cm2 (10 to 16<), respectively. Our dose results are among the values found in other international studies; however, there is great potential for dose optimization.

Diagnostic Reference Levels in Interventional Pediatric Cardiology: Two-Year Experience in a Tertiary Referral Hospital in Latin America.

The goal of the present study was to propose the first local diagnostic reference levels (DRLs) for interventional pediatric cardiology procedures in a large hospital in Colombia. The data collection period was from April 2020 to July 2022. The local DRLs were calculated as the 3rd quartile of patient-dose distributions for the kerma-area product (Pka) values. The sample of collected clinical procedures (255) was divided into diagnostic and therapeutic procedures and grouped into five weight and five age bands. The Pka differences found between diagnostic and therapeutic procedures were statistically significant in all weight and age bands, except for the 1-5-year age group. The local DRLs for weight bands were 3.82 Gy·cm2 (<5 kg), 7.39 Gy·cm2 (5-<15 kg), 19.72 Gy·cm2 (15-<30 kg), 28.99 Gy·cm2 (30-<50 kg), and 81.71 Gy·cm2 (50-<80 kg), respectively. For age bands, the DRLs were 3.97 Gy·cm2 (<1 y), 9.94 Gy·cm2 (1-<5 y), 20.82 Gy·cm2 (5-<10 y), 58.00 Gy·cm2 (10-<16 y), and 31.56 Gy·cm2 (<16 y), respectively. In conclusion, when comparing our results with other existing DRL values, we found that they are similar to other centers and thus there is scope to continue optimizing the radiation dose values. This will contribute to establishing national DRLs for Colombia in the near future.

Exacerbated response to oxidative stress in the Retinitis Pigmentosa CerklKD/KO mouse model triggers retinal degeneration pathways upon acute light stress.

The retina is particularly vulnerable to genetic and environmental alterations that generate oxidative stress and cause cellular damage in photoreceptors and other retinal neurons, eventually leading to cell death. CERKL (CERamide Kinase-Like) mutations cause Retinitis Pigmentosa and Cone-Rod Dystrophy in humans, two disorders characterized by photoreceptor degeneration and progressive vision loss. CERKL is a resilience gene against oxidative stress, and its overexpression protects cells from oxidative stress-induced apoptosis. Besides, CERKL contributes to stress granule-formation and regulates mitochondrial dynamics in the retina. Using the CerklKD/KO albino mouse model, which recapitulates the human disease, we aimed to study the impact of Cerkl knockdown on stress response and activation of photoreceptor death mechanisms upon light/oxidative stress. After acute light injury, we assessed immediate or late retinal stress response, by combining both omic and non-omic approaches. Our results show that Cerkl knockdown increases ROS levels and causes a basal exacerbated stress state in the retina, through alterations in glutathione metabolism and stress granule production, overall compromising an adequate response to additional oxidative damage. As a consequence, several cell death mechanisms are triggered in CerklKD/KO retinas after acute light stress. Our studies indicate that Cerkl gene is a pivotal player in regulating light-challenged retinal homeostasis and shed light on how mutations in CERKL lead to blindness by dysregulation of the basal oxidative stress response in the retina.

New Optimization Strategies on Radiation Protection in Fluoroscopy-Guided Interventional Procedures in Pediatrics.

The term fluoroscopically guided interventional procedure describes a clinical practice in medicine, where fluoroscopic systems are used to conduct diagnostic procedures or provide image guidance for therapeutic interventional procedures performed via percutaneous or other access routes [...].

Deficiency of the ywhaz gene, involved in neurodevelopmental disorders, alters brain activity and behaviour in zebrafish.

Genetic variants in YWHAZ contribute to psychiatric disorders such as autism spectrum disorder and schizophrenia, and have been related to an impaired neurodevelopment in humans and mice. Here, we have used zebrafish to investigate the mechanisms by which YWHAZ contributes to neurodevelopmental disorders. We observed that ywhaz expression was pan-neuronal during developmental stages and restricted to Purkinje cells in the adult cerebellum, cells that are described to be reduced in number and size in autistic patients. We then performed whole-brain imaging in wild-type and ywhaz CRISPR/Cas9 knockout (KO) larvae and found altered neuronal activity and connectivity in the hindbrain. Adult ywhaz KO fish display decreased levels of monoamines in the hindbrain and freeze when exposed to novel stimuli, a phenotype that can be reversed with drugs that target monoamine neurotransmission. These findings suggest an important role for ywhaz in establishing neuronal connectivity during development and modulating both neurotransmission and behaviour in adults.