Serum myostatin as a candidate disease severity and progression biomarker of spinal muscular atrophy.

The identification of biomarkers for spinal muscular atrophy is crucial for predicting disease progression, severity, and response to new disease-modifying therapies. This study aimed to investigate the role of serum levels of myostatin and follistatin as biomarkers for spinal muscular atrophy, considering muscle atrophy secondary to denervation as the main clinical manifestation of the disease. The study evaluated the differential gene expression of myostatin and follistatin in a lesional model of gastrocnemius denervation in mice, as well as in a meta-analysis of three datasets in transgenic mice models of spinal muscular atrophy, and in two studies involving humans with spinal muscular atrophy. Subsequently, a case-control study involving 27 spinal muscular atrophy patients and 27 controls was conducted, followed by a 12-month cohort study with 25 spinal muscular atrophy cases. Serum levels of myostatin and follistatin were analysed using enzyme-linked immunosorbent assay at a single centre in southern Brazil. Skeletal muscle gene expression of myostatin decreased and of follistatin increased following lesional muscle denervation in mice, consistent with findings in the spinal muscular atrophy transgenic mice meta-analysis and in the iliopsoas muscle of five patients with spinal muscular atrophy type 1. Median serum myostatin levels were significantly lower in spinal muscular atrophy patients (98 pg/mL; 5-157) compared to controls (412 pg/mL; 299-730) (P < 0.001). Lower myostatin levels were associated with greater disease severity based on clinician-rated outcomes (Rho = 0.493-0.812; P < 0.05). After 12 months, there was a further reduction in myostatin levels among spinal muscular atrophy cases (P = 0.021). Follistatin levels did not differ between cases and controls, and no significant changes were observed over time. The follistatin:myostatin ratio was significantly increased in spinal muscular atrophy subjects and inversely correlated with motor severity. Serum myostatin levels show promise as a novel biomarker for evaluating the severity and progression of spinal muscular atrophy. The decrease in myostatin levels and the subsequent favourable environment for muscle growth may be attributed to denervation caused by motor neuron dysfunction.

Bioinformatics Methods for Transcriptome Analysis on Teratogenesis Testing.

Teratogenesis testing can be challenging due to the limitations of both in vitro and in vivo models. Test-systems, based especially on human embryonic cells, have been helping to overcome the difficulties when allied to omics strategies, such as transcriptomics. In these test-systems, cells exposed to different compounds are then analyzed in microarray or RNA-seq platforms regarding the impacts of the potential teratogens in the gene expression. Nevertheless, microarray and RNA-seq dataset processing requires computational resources and bioinformatics knowledge. Here, a pipeline for microarray and RNA-seq processing is presented, aiming to help researchers from any field to interpret the main transcriptome results, such as differential gene expression, enrichment analysis, and statistical interpretation. This chapter also discusses the main difficulties that can be encountered in a transcriptome analysis and the better alternatives to overcome these issues, describing both programming codes and user-friendly tools. Finally, specific issues in the teratogenesis field, such as time-course analysis, are also described, demonstrating how the pipeline can be applied in these studies.

Brazilian women in Bioinformatics: Challenges and opportunities.

Bioinformatics is a growing research field that received great notoriety in the years of the COVID-19 pandemic. It is a very integrative area, comprising professionals from science, technology, engineering, and mathematics (STEM). In agreement with the other STEM areas, several women have greatly contributed to bioinformatics ascension; however, they had to surpass prejudice and stereotypes to achieve recognition and leadership positions, a path that studies have demonstrated to be more comfortable to their male colleagues. In this review, we discuss the several difficulties that women in STEM, including bioinformatics, surpass during their careers. First, we present a historical context on bioinformatics and the main applications for this area. Then, we discuss gender disparity in STEM and present the challenges that still contribute to women's inequality in STEM compared to their male colleagues. We also present the opportunities and the transformation that we can start, acting in academia, inside the family and school environments, and as a society, hence contributing to gender equality in STEM. Finally, we discuss specific challenges in the bioinformatics field and how we can act to overcome them, especially in low and middle-income countries, such as Brazil.

A New Strategy for the Old Challenge of Thalidomide: Systems Biology Prioritization of Potential Immunomodulatory Drug (IMiD)-Targeted Transcription Factors.

Several molecular mechanisms of thalidomide embryopathy (TE) have been investigated, from anti-angiogenesis to oxidative stress to cereblon binding. Recently, it was discovered that thalidomide and its analogs, named immunomodulatory drugs (IMiDs), induced the degradation of C2H2 transcription factors (TFs). This mechanism might impact the strict transcriptional regulation of the developing embryo. Hence, this study aims to evaluate the TFs altered by IMiDs, prioritizing the ones associated with embryogenesis through transcriptome and systems biology-allied analyses. This study comprises only the experimental data accessed through bioinformatics databases. First, proteins and genes reported in the literature as altered/affected by the IMiDs were annotated. A protein systems biology network was evaluated. TFs beta-catenin (CTNNB1) and SP1 play more central roles: beta-catenin is an essential protein in the network, while SP1 is a putative C2H2 candidate for IMiD-induced degradation. Separately, the differential expressions of the annotated genes were analyzed through 23 publicly available transcriptomes, presenting 8624 differentially expressed genes (2947 in two or more datasets). Seventeen C2H2 TFs were identified as related to embryonic development but not studied for IMiD exposure; these TFs are potential IMiDs degradation neosubstrates. This is the first study to suggest an integration of IMiD molecular mechanisms through C2H2 TF degradation.

Precision medicine implementation challenges for APOL1 testing in chronic kidney disease in admixed populations.

Chronic Kidney Disease (CKD) is a public health problem that presents genetic and environmental risk factors. Two alleles in the Apolipoprotein L1 (APOL1) gene were associated with chronic kidney disease; these alleles are common in individuals of African ancestry but rare in European descendants. Genomic studies on Afro-Americans have indicated a higher prevalence and severity of chronic kidney disease in people of African ancestry when compared to other ethnic groups. However, estimates in low- and middle-income countries are still limited. Precision medicine approaches could improve clinical outcomes in carriers of risk alleles in the Apolipoprotein L1 gene through early diagnosis and specific therapies. Nevertheless, to enhance the definition of studies on these variants, it would be necessary to include individuals with different ancestry profiles in the sample, such as Latinos, African Americans, and Indigenous peoples. There is evidence that measuring genetic ancestry improves clinical care for admixed people. For chronic kidney disease, this knowledge could help establish public health strategies for monitoring patients and understanding the impact of the Apolipoprotein L1 genetic variants in admixed populations. Therefore, researchers need to develop resources, methodologies, and incentives for vulnerable and disadvantaged communities, to develop and implement precision medicine strategies and contribute to consolidating diversity in science and precision medicine in clinical practice.

Efficiency of ITS sequences for DNA barcoding in Passiflora (Passifloraceae).

DNA barcoding is a technique for discriminating and identifying species using short, variable, and standardized DNA regions. Here, we tested for the first time the performance of plastid and nuclear regions as DNA barcodes in Passiflora. This genus is a largely variable, with more than 900 species of high ecological, commercial, and ornamental importance. We analyzed 1034 accessions of 222 species representing the four subgenera of Passiflora and evaluated the effectiveness of five plastid regions and three nuclear datasets currently employed as DNA barcodes in plants using barcoding gap, applied similarity-, and tree-based methods. The plastid regions were able to identify less than 45% of species, whereas the nuclear datasets were efficient for more than 50% using "best match" and "best close match" methods of TaxonDNA software. All subgenera presented higher interspecific pairwise distances and did not fully overlap with the intraspecific distance, and similarity-based methods showed better results than tree-based methods. The nuclear ribosomal internal transcribed spacer 1 (ITS1) region presented a higher discrimination power than the other datasets and also showed other desirable characteristics as a DNA barcode for this genus. Therefore, we suggest that this region should be used as a starting point to identify Passiflora species.