Broken silence: 22,841 predicted deleterious synonymous variants identified in the human exome through computational analysis.

Synonymous single nucleotide variants (sSNVs) do not alter the primary structure of a protein, thus it was previously accepted that they were neutral. Recently, several studies demonstrated their significance to a range of diseases. Still, variant prioritization strategies lack focus on sSNVs. Here, we identified 22,841 deleterious synonymous variants in 125,748 human exomes using two in silico predictors (SilVA and CADD). While 98.2% of synonymous variants are classified as neutral, 1.8% are predicted to be deleterious, yielding an average of 9.82 neutral and 0.18 deleterious sSNVs per exome. Further investigation of prediction features via Heterogeneous Ensemble Feature Selection revealed that impact on amino acid sequence and conservation carry the most weight for a deleterious prediction. Thirty nine detrimental sSNVs are not rare and are located on disease associated genes. Ten distinct putatively non-deleterious sSNVs are likely to be under positive selection in the North-Western European and East Asian populations. Taken together our analysis gives voice to the so-called silent mutations as we propose a robust framework for evaluating the deleteriousness of sSNVs in variant prioritization studies.

Regulatory Framework, Challenges, and Initial Strategic Planning for Advanced Therapy Products (PTAs) Development in Brazil.

Advanced Therapies are a class of innovative complex biological products used for therapeutic purposes, encompassing cell therapy, tissue engineering, and gene therapy products. These are promising therapeutic strategies for several complex diseases with low or non-existent therapeutic alternatives. The proper transposition of basic research in this area into medicinal products must comply with regulatory requirements. Here we review the main regulatory recommendations, emphasizing on the Brazilian regulation. The critical points are the manufacturing process, challenges in characterizing the product, development of non-clinical trials, lack of adequate animal models representative of the clinical situation, and absence of valid and measurable therapeutic endpoints. Based on that, we propose a framework for strategic planning of pre-clinical studies in this field. The detailed example involves producing a nonviral vector-based gene editing product, but the regulations and methods may be extrapolated for developing different types of advanced therapies.

CRISPR/Cas patents and health-related publications in South America.

CRISPR/Cas is being increasingly used for various applications. However, different countries introduce new technologies at different paces and purposes. This study reviews research progress using the CRISPR/Cas system in South America, focusing on health-related applications. The PubMed database was used to identify relevant articles about gene editing with CRISPR/Cas, whereas patents were searched in the Patentscope database. In addition, ClinicalTrials.gov was used to find information on active and recruiting clinical trials. A total of 668 non-duplicated articles (extracted from PubMed) and 225 patents (not all health-related) were found. One hundred ninety-two articles on health-related applications of CRISPR/Cas were analyzed in detail. In 95 out of these, more than 50% of the authors were affiliated with South American institutions. Experimental CRISPR/Cas studies target different diseases, particularly cancer, neurological, and endocrine disorders. Most patents refer to generic applications, but those with clear disease indications are for inborn errors of metabolism, ophthalmological, hematological, and immunological disorders. No clinical trials were found involving Latin American countries. Although research on gene editing in South America is advancing, our data show the low number of national innovations protected by intellectual property in this field.

Analysis of the interval between submission and publication in genetics journals.

One of the main factors that attracts authors to choose a journal is the time interval between submission and publication, which varies between journals and subject matter. Here, we evaluated the time intervals between submission and publication according to journal impact factor and continent of author's affiliation, considering articles with authors from single or multiple continents. Altogether, 72 journals indexed in the Web of Science database within the subject matter "Genetics and Heredity", divided by impact factor into four quartiles and randomly selected were analyzed for time intervals from article submission to publication. Data from a total of 46,349 articles published from 2016 to 2020 were collected and analyzed considering the following time intervals: submission to acceptance (SA), acceptance to publication (AP) and submission to publication (SP). The median of the quartiles for the SP interval was 166 (IQR [118-225]) days for Q1, 147 (IQR [103-206]) days for Q2, 161 (IQR [116-226]) days for Q3 and 137 (IQR [69-264]) days for Q4, showing a significant difference among quartiles (p < 0.001). In Q4, median interval of time was shorter in interval SA but longer in interval AP, and overall, articles in Q4 had the shortest interval of time in SP. A potential association of the median time interval and authors' continent was analysed and no significant difference was observed between articles with authors from single versus multiple continents or between continents in articles with authors from only one continent. However, in journals from Q4, time from submission to publication was longer for articles with authors from North America and Europe than from other continents, although the difference was not significant. Finally, articles of authors from the African continent had the smallest representation in journals from Q1-Q3 and articles from Oceania were underrepresented in group Q4. The study provides a global analysis of the total time required for submission, acceptance and publication in journals in the field of genetics and heredity. Our results may contribute in the development of strategies to expedite the process of scientific publishing in the field, and to promote equity in knowledge production and dissemination for researchers from all continents.

Identification of adverse drug reactions that may be related to pharmacogenetics in a public hospital in the South of Brazil.

BACKGROUND: Adverse drug reactions (ADRs) are of great concern in clinical practice. Pharmacogenetics can identify individuals and groups at increased risk of developing ADRs, enabling treatment adjustments to improve outcomes. The study aimed to determine the prevalence of ADRs related to drugs with pharmacogenetic evidence level 1A in a public hospital in Southern Brazil. RESEARCH DESIGN AND METHODS: ADR information was collected from the pharmaceutical registries from 2017 to 2019. Drugs that have pharmacogenetic evidence level 1A were selected. Public genomic databases were used to estimate the genotypes/phenotypes frequency. RESULTS: During the period, 585 ADRs were spontaneously notified. Most were moderate (76.3%), whereas severe reactions accounted for 33.8%. Additionally, 109 ADRs caused by 41 drugs presented pharmacogenetic evidence level 1A, representing 18.6% of all notified reactions. Depending on the drug-gene pair, up to 35% of individuals from Southern Brazil could be at risk of developing ADRs. CONCLUSIONS: Relevant amount of ADRs were related to drugs with pharmacogenetic recommendations on drug labels and/or guidelines. Genetic information could guide and improve clinical outcomes, decreasing ADR incidence and reducing treatment costs.

Drug Repositioning Applied to Cardiovascular Disease in Mucopolysaccharidosis.

Mucopolysaccharidoses (MPS) are genetic metabolic diseases characterized by defects in the activity of lysosomal hydrolases. In MPS, secondary cell disturbance affects pathways related to cardiovascular disorders. Hence, the study aimed to identify MPS-related drugs targeting cardiovascular disease and select a list of drugs for repositioning. We obtained a list of differentially expressed genes and pathways. To identify drug perturbation-driven gene expression and drug pathways interactions, we used the CMAP and LINCS databases. For molecular docking, we used the DockThor web server. Our results suggest that pirfenidone and colchicine are promising drugs to treat cardiovascular disease in MPS patients. We also provide a brief description of good practices for the repositioning analysis. Furthermore, the list of drugs and related MPS-enriched genes could be helpful to new treatments and considered for pathophysiological studies.

Gene editing strategies to treat lysosomal disorders: The example of mucopolysaccharidoses.

Lysosomal storage disorders are a group of progressive multisystemic hereditary diseases with a combined incidence of 1:4,800. Here we review the clinical and molecular characteristics of these diseases, with a special focus on Mucopolysaccharidoses, caused primarily by the lysosomal storage of glycosaminoglycans. Different gene editing techniques can be used to ameliorate their symptoms, using both viral and nonviral delivery methods. Whereas these are still being tested in animal models, early results of phase I/II clinical trials of gene therapy show how this technology may impact the future treatment of these diseases. Hurdles related to specific hard-to-reach organs, such as the central nervous system, heart, joints, and the eye must be tackled. Finally, the regulatory framework necessary to advance into clinical practice is also discussed.

Protection is not always a good thing: The immune system's impact on gene therapy.

There are many clinical trials underway for the development of gene therapies, and some have resulted in gene therapy products being commercially approved already. Significant progress was made to develop safer and more effective strategies to deliver and regulate genetic products. An unsolved aspect is the immune system, which can affect the efficiency of gene therapy in different ways. Here we present an overview of approved gene therapy products and the immune response elicited by gene delivery systems. These include responses against the vector or its content after delivery and against the product of the corrected gene. Strategies to overcome the hurdles include hiding the vector or/and the transgene product from the immune system and hiding the immune system from the vector/transgene product. Combining different strategies, such as patient screening and intelligent vector design, gene therapy is set to make a difference in the life of patients with severe genetic diseases.

Sales of "COVID kit" drugs and adverse drug reactions reported by the Brazilian Health Regulatory Agency.

Off-label use of azithromycin, hydroxychloroquine, and ivermectin (the "COVID kit") has been suggested for COVID-19 treatment in Brazil without clinical or scientific evidence of efficacy. These drugs have known adverse drug reactions (ADR). This study aimed to analyze if the sales of drugs in the "COVID kit" are correlated to the reported number of ADR after the COVID-19 pandemic began. Data was obtained from the Brazilian Health Regulatory Agency (Anvisa) website on reported sales and ADRs for azithromycin, hydroxychloroquine, and ivermectin for all Brazilian states. The period from March 2019 to February 2020 (before the pandemic) was compared to that from March 2020 to February 2021 (during the pandemic). Trend adjustment was performed for time series data and cross-correlation analysis to investigate correlation between sales and ADR within the same month (lag 0) and in the following months (lag 1 and lag 2). Spearman's correlation coefficient was used to assess the magnitude of the correlations. After the pandemic onset, sales of all investigated drugs increased significantly (69.75% for azithromycin, 10,856,481.39% for hydroxychloroquine, and 12,291,129.32% for ivermectin). ADR levels of all medications but azithromycin were zero before the pandemic, but increased after its onset. Cross-correlation analysis was significant in lag 1 for all drugs nationwide. Spearman's correlation was moderate for azithromycin and hydroxychloroquine but absent for ivermectin. Data must be interpreted cautiously since no active search for ADR was performed. Our results show that the increased and indiscriminate use of "COVID kit" during the pandemic correlates to an increased occurrence of ADRs.

In silico analysis of potential off-target sites to gene editing for Mucopolysaccharidosis type I using the CRISPR/Cas9 system: Implications for population-specific treatments.

Mucopolysaccharidosis type I (MPS I) is caused by alpha-L-iduronidase deficiency encoded by the IDUA gene. Therapy with CRISPR/Cas9 is being developed for treatment, however a detailed investigation of off-target effects must be performed. This study aims to evaluate possible off-targets for a sgRNA aiming to correct the most common variant found in MPS I patients (p.Trp402*). A total of 272 potential off-target sequences was obtained and 84 polymorphic sites were identified in these sequences with a frequency equal to or greater than 1% in at least one of the populations. In the majority of cases, polymorphic sites decrease the chance of off-target cleavage and a new PAM was created, which indicates the importance of such analysis. This study highlights the importance of screening off-targets in a population-specific context using Mucopolysaccharidosis type I as an example of a problem that concerns all therapeutic treatments. Our results can have broader applications for other targets already clinically in use, as they could affect CRISPR/Cas9 safety and efficiency.

Brain and visceral gene editing of mucopolysaccharidosis I mice by nasal delivery of the CRISPR/Cas9 system.

BACKGROUND: Mucopolysaccharidosis type I (MPS I) is an inherited disease caused by deficiency of the enzyme alpha-l-iduronidase (IDUA). MPS I affects several tissues, including the brain, leading to cognitive impairment in the severe form of the disease. Currently available treatments do not reach the brain. Therefore, in this study, we performed nasal administration (NA) of liposomal complexes carrying two plasmids encoding for the CRISPR/Cas9 system and for the IDUA gene targeting the ROSA26 locus, aiming at brain delivery in MPS I mice. METHODS: Liposomes were prepared by microfluidization, and the plasmids were complexed to the formulations by adsorption. Physicochemical characterization of the formulations and complexes, in vitro permeation, and mucoadhesion in porcine nasal mucosa (PNM) were assessed. We performed NA repeatedly for 30 days in young MPS I mice, which were euthanized at 6 months of age after performing behavioral tasks, and biochemical and molecular aspects were evaluated. RESULTS: Monodisperse mucoadhesive complexes around 110 nm, which are able to efficiently permeate the PNM. In animals, the treatment led to a modest increase in IDUA activity in the lung, heart, and brain areas, with reduction of glycosaminoglycan (GAG) levels in serum, urine, tissues, and brain cortex. Furthermore, treated mice showed improvement in behavioral tests, suggesting prevention of the cognitive damage. CONCLUSION: Nonviral gene editing performed through nasal route represents a potential therapeutic alternative for the somatic and neurologic symptoms of MPS I and possibly for other neurological disorders.

Frequency of DPYD gene variants and phenotype inference in a Southern Brazilian population.

Fluoropyrimidines are chemotherapy drugs that may cause severe adverse events, and their metabolism occurs by dihydropyrimidine deydrogenase (DPD), coded by DPYD. Variants in the DPYD were associated to a greater risk of toxicity. Our aim was to determine the frequency of the most relevant DPYD alleles according to CPIC guidelines (DPYD*2A-rs3918290, DPYD*13-rs55886062, rs67376798, and HapB3-rs75017182) in a sample of 800 healthy Southern Brazilians. Frequencies for rs3918290, rs75017182, and rs67376798 were 0.25%, 1.06%, and 0.38%, respectively. No rs55886062 allele was detected. In total, 3.4% of individuals were classified as intermediate metabolizers. Frequencies for rs3918290, rs55886062, and rs67376798 were similar to those found in non-Finnish Europeans; however, rs75017182 was less frequent when compared to non-Finnish Europeans, but more frequent than in Africans and East Asians. rs3918290 and rs67376798 also presented higher frequency when compared to Africans. The Latino population was the only one that did not differ from our sample in any variant analyzed. The frequencies for all the other populations (non-Finnish European, African, South Asian, and East Asian) presented differences from our sample in at least one variant. rs115232898 was not analyzed in the present study. Cost-effective studies should be performed to evaluate the implementation of these tests in the clinical practice in the Southern Brazil.

Risk factors associated with the development of oral mucositis in pediatric oncology patients: Systematic review and meta-analysis.

OBJECTIVES: Oral mucositis (OM) is an acute toxicity related to cancer treatment. This systematic review aimed to identify potential risk factors associated with the development of OM in pediatric cancer patients. METHODS: A search was performed in four electronic databases to identify studies that analyzed risk factors for OM in pediatric cancer patients. RESULTS: Nineteen articles were included. The incidence of OM ranged from 20% to 80.4%. Chemotherapeutic agents were potential risk factors for OM in eight (42%) studies. Hematological, hepatic, and renal parameters were also considered in eight (42%) studies, while specific individual factors were reported in five (26.3%) studies. Baseline disease, oral microbiota, genetic profile, and biomarkers were reported in four (21.5%) studies each. Meta-analysis showed that groups submitted to high-risk chemotherapy for OM had a 2.79-fold increased risk of OM. CONCLUSIONS: Identifying risk factors for OM is essential in order to allow individualized and early prevention treatment.

Sales of "COVID kit" drugs and adverse drug reactions reported by the Brazilian Health Regulatory Agency / Vendas de "kit-COVID" e reações adversas a esses medicamentos relatadas pela Agência Nacional de Vigilância Sanitária / Ventas de medicamentos del "kit-COVID" y reacciones adversas a los medicamentos notificadas por la Agencia Nacional de Vigilancia Sanitaria

Off-label use of azithromycin, hydroxychloroquine, and ivermectin (the "COVID kit") has been suggested for COVID-19 treatment in Brazil without clinical or scientific evidence of efficacy. These drugs have known adverse drug reactions (ADR). This study aimed to analyze if the sales of drugs in the "COVID kit" are correlated to the reported number of ADR after the COVID-19 pandemic began. Data was obtained from the Brazilian Health Regulatory Agency (Anvisa) website on reported sales and ADRs for azithromycin, hydroxychloroquine, and ivermectin for all Brazilian states. The period from March 2019 to February 2020 (before the pandemic) was compared to that from March 2020 to February 2021 (during the pandemic). Trend adjustment was performed for time series data and cross-correlation analysis to investigate correlation between sales and ADR within the same month (lag 0) and in the following months (lag 1 and lag 2). Spearman's correlation coefficient was used to assess the magnitude of the correlations. After the pandemic onset, sales of all investigated drugs increased significantly (69.75% for azithromycin, 10,856,481.39% for hydroxychloroquine, and 12,291,129.32% for ivermectin). ADR levels of all medications but azithromycin were zero before the pandemic, but increased after its onset. Cross-correlation analysis was significant in lag 1 for all drugs nationwide. Spearman's correlation was moderate for azithromycin and hydroxychloroquine but absent for ivermectin. Data must be interpreted cautiously since no active search for ADR was performed. Our results show that the increased and indiscriminate use of "COVID kit" during the pandemic correlates to an increased occurrence of ADRs.

No Brasil, o uso off label de azitromicina, hidroxicloroquina e ivermectina (o "kit-COVID") foi sugerido para tratar COVID-19 sem que tivéssemos evidências clínicas ou científicas de sua eficácia. Estas drogas têm causado reações adversas (RA) em quem as tomam. Este estudo almejou analisar se a venda dos medicamentos que compõem o "kit-COVID" correlaciona-se com o número relatado de RAs após o início da pandemia da COVID-19. Os dados sobre vendas e RA associados a azitromicina, hidroxicloroquina e ivermectina foram obtidos no site da Agência Nacional de Vigilância Sanitária (Anvisa) para todos os estados brasileiros. Comparamos o período entre março de 2019 e fevereiro de 2020 (antes da pandemia) ao de março de 2020 a fevereiro de 2021 (durante a pandemia). Ajustamos tendências para os dados de séries temporais e as análises de correlação cruzada para investigar a correlação entre vendas e RA em um mesmo mês (lag 0) e nos seguintes (lag 1 e 2). O coeficiente de correlação de Spearman foi utilizado para avaliar a magnitude das correlações. Após o início da pandemia, as vendas de todos os medicamentos investigados aumentaram significativamente (69,75% para azitromicina, 10.856.481,39% para hidroxicloroquina e 12.291.129,32% para ivermectina). Os níveis de RAs de todos os medicamentos (com exceção de azitromicina) eram zero antes da pandemia mas aumentaram após seu início. A análise de correlação cruzada foi significativa no lag 1 para todas as drogas em todo o país. A correlação de Spearman foi moderada para azitromicina e hidroxicloroquina, mas ausente para ivermectina. Os dados devem ser interpretados com cautela, uma vez que não realizamos uma busca ativa por RA. Nossos resultados mostram que o uso aumentado e indiscriminado do "kit-COVID" durante a pandemia se correlaciona com uma ocorrência aumentada de RAs.

Se ha sugerido el uso fuera de lo establecido de azitromicina, hidroxicloroquina e ivermectina (el "kit-COVID") para el tratamiento de la COVID-19 en Brasil sin evidencia clínica o científica de su eficacia. Estos medicamentos tienen reacciones adversas (RAM) conocidas. Este estudio pretendía analizar si las ventas de medicamentos del "kit-COVID" están correlacionadas con el número de reacciones adversas notificadas tras el inicio de la pandemia de COVID-19. Los datos se obtuvieron del sitio web de la Agencia Nacional de Vigilancia Sanitaria (Anvisa) sobre las ventas y las RAM notificadas para la azitromicina, la hidroxicloroquina y la ivermectina para todos los estados brasileños. Se comparó el periodo de marzo de 2019 a febrero de 2020 (antes de la pandemia) con el de marzo de 2020 a febrero de 2021 (durante la pandemia). Se realizó un ajuste de tendencia para los datos de las series de tiempo y un análisis de correlación cruzada para investigar la correlación entre las ventas y la RAM dentro del mismo mes (lag 0) y en los meses siguientes (lag 1 y lag 2). Se utilizó el coeficiente de correlación de Spearman para evaluar la magnitud de las correlaciones. Tras el inicio de la pandemia, las ventas de todos los medicamentos investigados aumentaron significativamente (69,75% para la azitromicina, 10.856.481,39% para la hidroxicloroquina y 12.291.129,32% para la ivermectina). Los niveles de RAM de todos los medicamentos, excepto la azitromicina, eran nulos antes de la pandemia, pero aumentaron tras su inicio. El análisis de correlación cruzada fue significativo en el lag 1 para todos los medicamentos a nivel nacional. La correlación de Spearman fue moderada para la azitromicina y la hidroxicloroquina, pero no para la ivermectina. Los datos deben interpretarse con cautela, ya que no se realizó una búsqueda activa de RAM. Nuestros resultados muestran que el uso creciente e indiscriminado del "kit-COVID" durante la pandemia se correlaciona con una mayor aparición de las RAM.

Hearing Impairment in Mucopolysaccharidosis: A Systems Biology Approach

Abstract Mucopolysaccharidoses (MPS) are lysosomal diseases caused by deficiencies in lysosomal enzymes involved in the degradation of glycosaminoglycans (GAGs). Sensorineural hearing impairment is a common feature in MPS patients, but there is no consensus on its etiology. For this reason, we aimed to identify genes and pathways related to hearing loss and to correlate them with gene expression data in MPS. We used HPO and Disgenet to identify candidate genes. We constructed the network with string and Cytoscape, and hub genes were identified in Cytohubba. Expression data were obtained from the MPSBase website. We found the NDUFA gene family as the major hub genes and 114 enriched pathways related to hearing loss. These genes and biological pathways may serve as potential candidates for clinical studies to better understand hearing impairment mechanisms in lysosomal storage diseases like mucopolysaccharidosis.

Disruption of morphogenic and growth pathways in lysosomal storage diseases.

The lysosome achieved a new protagonism that highlights its multiple cellular functions, such as in the catabolism of complex substrates, nutrient sensing, and signaling pathways implicated in cell metabolism and growth. Lysosomal storage diseases (LSDs) cause lysosomal accumulation of substrates and deficiency in trafficking of macromolecules. The substrate accumulation can impact one or several pathways which contribute to cell damage. Autophagy impairment and immune response are widely studied, but less attention is paid to morphogenic and growth pathways and its impact on the pathophysiology of LSDs. Hedgehog pathway is affected with abnormal expression and changes in distribution of protein levels, and a reduced number and length of primary cilia. Moreover, growth pathways are identified with delay in reactivation of mTOR that deregulate termination of autophagy and reformation of lysosomes. Insulin resistance caused by changes in lipids rafts has been described in different LSDs. While the genetic and biochemical bases of deficient proteins in LSDs are well understood, the secondary molecular mechanisms that disrupt wider biological processes associated with LSDs are only now becoming clearer. Therefore, we explored how specific signaling pathways can be related to specific LSDs, showing that a system medicine approach could be a valuable tool for the better understanding of LSD pathogenesis. This article is categorized under: Metabolic Diseases > Molecular and Cellular Physiology.

Which Is the Best In Silico Program for the Missense Variations in IDUA Gene? A Comparison of 33 Programs Plus a Conservation Score and Evaluation of 586 Missense Variants.

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disease characterized by the deficiency of alpha-L-iduronidase (IDUA), an enzyme involved in glycosaminoglycan degradation. More than 200 disease-causing variants have been reported and characterized in the IDUA gene. It also has several variants of unknown significance (VUS) and literature conflicting interpretations of pathogenicity. This study evaluated 586 variants obtained from the literature review, five population databases, in addition to dbSNP, Human Genome Mutation Database (HGMD), and ClinVar. For the variants described in the literature, two datasets were created based on the strength of the criteria. The stricter criteria subset had 108 variants with expression study, analysis of healthy controls, and/or complete gene sequence. The less stringent criteria subset had additional 52 variants found in the literature review, HGMD or ClinVar, and dbSNP with an allele frequency higher than 0.001. The other 426 variants were considered VUS. The two strength criteria datasets were used to evaluate 33 programs plus a conservation score. BayesDel (addAF and noAF), PON-P2 (genome and protein), and ClinPred algorithms showed the best sensitivity, specificity, accuracy, and kappa value for both criteria subsets. The VUS were evaluated with these five algorithms. Based on the results, 122 variants had total consensus among the five predictors, with 57 classified as predicted deleterious and 65 as predicted neutral. For variants not included in PON-P2, 88 variants were considered deleterious and 92 neutral by all other predictors. The remaining 124 did not obtain a consensus among predictors.

MPSBase: Comprehensive repository of differentially expressed genes for mucopolysaccharidoses.

Mucopolysaccharidoses (MPS) are lysosomal storage diseases (LSDs) caused by the deficiency of enzymes essential for the metabolism of extracellular matrix components called glycosaminoglycans (GAGs). To understand the physiopathology and alterations due to the lysosomal accumulation resulting from enzymatic deficiencies and their secondary outcomes can improve the diagnosis and treatment of rare genetic diseases. This work presents a database for differentially expressed genes from different public MPS data. We developed our database, including 13 studies previously deposited in the GEO (https://www.ncbi.nlm.nih.gov/geo/). The website is hosted in the UFRGS data processing center (CPD) and is available at . The site was constructed in PHP, and the analyses were performed in R. The organisms represented by the datasets are Canis lupus familiaris, Homo sapiens, Mus musculus, and Rattus norvegicus. The user can search for the differentially expressed genes and ontologies by species, MPS type, or tissue type. For each comparison, a heatmap with the 50 top differentially expressed genes is available as well as dot plots for the 30 top ontologies divided by biological process, cellular component, KEGG pathways, and molecular function. This data is also fully available in tables. There are 54 possible comparisons involving about 5000 to 10,000 genes each. This website is the only specific database for MPS with filtering and presenting their results in a one-click approach to the best of our knowledge. The development of such analytical and automated strategies accessible to health professionals is essential for fostering MPS research. The MPSBase is a web user-friendly, comprehensive repository of differentially expressed genes and ontologies regarding the MPS data.

Genome editing in mucopolysaccharidoses and mucolipidoses.

Mucopolysaccharidoses (MPS) and mucolipidoses (ML) are disorders that alter lysosome function. While MPS are caused by mutation in enzymes that degrade glycosaminoglycans, the ML are disorders characterized by reduced function in the phosphotransferase enzyme. Multiple clinical features are associated with these diseases and the exact mechanisms that could explain such different clinical manifestations in patients are still unknown. Furthermore, there are no curative treatment for any of MPS and ML conditions so far. Gene editing holds promise as a tool for the creation of cell and animal models to help explain disease pathogenesis, as well as a platform for gene therapy. In this chapter, we discuss the main studies involving genome editing for MPS and the prospect applications for ML.

Fantastic databases and where to find them: Web applications for researchers in a rush.

Public databases are essential to the development of multi-omics resources. The amount of data created by biological technologies needs a systematic and organized form of storage, that can quickly be accessed, and managed. This is the objective of a biological database. Here, we present an overview of human databases with web applications. The databases and tools allow the search of biological sequences, genes and genomes, gene expression patterns, epigenetic variation, protein-protein interactions, variant frequency, regulatory elements, and comparative analysis between human and model organisms. Our goal is to provide an opportunity for exploring large datasets and analyzing the data for users with little or no programming skills. Public user-friendly web-based databases facilitate data mining and the search for information applicable to healthcare professionals. Besides, biological databases are essential to improve biomedical search sensitivity and efficiency and merge multiple datasets needed to share data and build global initiatives for the diagnosis, prognosis, and discovery of new treatments for genetic diseases. To show the databases at work, we present a a case study using ACE2 as example of a gene to be investigated. The analysis and the complete list of databases is available in the following website .