ABSTRACT
Phenylketonuria (PKU) is a genetic disorder caused by variations in the phenylalanine hydroxylase (PAH) gene. Among the 3369 reported PAH variants, 33.7% are missense alterations. Unfortunately, 30% of these missense variants are classified as variants of unknown significance (VUS), posing challenges for genetic risk assessment. In our study, we focused on analyzing 836 missense PAH variants following the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines specified by ClinGen PAH Variant Curation Expert Panel (VCEP) criteria. We utilized and compared variant annotator tools like Franklin and Varsome, conducted 3D structural analysis of PAH, and examined active and regulatory site hotspots. In addition, we assessed potential splicing effect of apparent missense variants. By evaluating phenotype data from 22962 PKU patients, our aim was to reassess the pathogenicity of missense variants. Our comprehensive approach successfully reclassified 309 VUSs out of 836 missense variants as likely pathogenic or pathogenic (37%), upgraded 370 likely pathogenic variants to pathogenic, and reclassified one previously considered likely benign variant as likely pathogenic. Phenotypic information was available for 636 missense variants, with 441 undergoing 3D structural analysis and active site hotspot identification for 180 variants. After our analysis, only 6% of missense variants were classified as VUSs, and three of them (c.23A>C/p.Asn8Thr, c.59_60delinsCC/p.Gln20Pro, and c.278A >T/p.Asn93Ile) may be influenced by abnormal splicing. Moreover, a pathogenic variant (c.168G>T/p.Glu56Asp) was identified to have a risk exceeding 98% for modifications of the consensus splice site, with high scores indicating a donor loss of 0.94. The integration of ACMG/AMP guidelines with in silico structural analysis and phenotypic data significantly reduced the number of missense VUSs, providing a strong basis for genetic counseling and emphasizing the importance of metabolic phenotype information in variant curation. This study also sheds light on the current landscape of PAH variants.
Subject(s)
Mutation, Missense , Phenotype , Phenylalanine Hydroxylase , Phenylketonurias , Humans , Phenylalanine Hydroxylase/genetics , Phenylalanine Hydroxylase/chemistry , Phenylketonurias/genetics , Phenylketonurias/pathology , Computer SimulationABSTRACT
The pathophysiology of nonketotic hyperglycinemia (NKH), a rare neuro-metabolic disorder associated with severe brain malformations and life-threatening neurological manifestations, remains incompletely understood. Therefore, a valid human neural model is essential. We aimed to investigate the impact of GLDC gene variants, which cause NKH, on cellular fitness during the differentiation process of human induced pluripotent stem cells (iPSCs) into iPSC-derived astrocytes and to identify sustainable mechanisms capable of overcoming GLDC deficiency. We developed the GLDC27-FiPS4F-1 line and performed metabolomic, mRNA abundance, and protein analyses. This study showed that although GLDC27-FiPS4F-1 maintained the parental genetic profile, it underwent a metabolic switch to an altered serine-glycine-one-carbon metabolism with a coordinated cell growth and cell cycle proliferation response. We then differentiated the iPSCs into neural progenitor cells (NPCs) and astrocyte-lineage cells. Our analysis showed that GLDC-deficient NPCs had shifted towards a more heterogeneous astrocyte lineage with increased expression of the radial glial markers GFAP and GLAST and the neuronal markers MAP2 and NeuN. In addition, we detected changes in other genes related to serine and glycine metabolism and transport, all consistent with the need to maintain glycine at physiological levels. These findings improve our understanding of the pathology of nonketotic hyperglycinemia and offer new perspectives for therapeutic options.
Subject(s)
Hyperglycinemia, Nonketotic , Induced Pluripotent Stem Cells , Humans , Hyperglycinemia, Nonketotic/genetics , Hyperglycinemia, Nonketotic/pathology , Glycine Dehydrogenase (Decarboxylating)/genetics , Astrocytes/pathology , Induced Pluripotent Stem Cells/pathology , Glycine , SerineABSTRACT
Inborn errors of metabolism (IEM) constitute a huge group of rare diseases affecting 1 in every 1000 newborns. Next-generation sequencing has transformed the diagnosis of IEM, leading to its proposed use as a second-tier technology for confirming cases detected by clinical/biochemical studies or newborn screening. The diagnosis rate is, however, still not 100%. This paper reports the use of a personalized multi-omics (metabolomic, genomic and transcriptomic) pipeline plus functional genomics to aid in the genetic diagnosis of six unsolved cases, with a clinical and/or biochemical diagnosis of galactosemia, mucopolysaccharidosis type I (MPS I), maple syrup urine disease (MSUD), hyperphenylalaninemia (HPA), citrullinemia, or urea cycle deficiency. Eight novel variants in six genes were identified: six (four of them deep intronic) located in GALE, IDUA, PTS, ASS1 and OTC, all affecting the splicing process, and two located in the promoters of IDUA and PTS, thus affecting these genes' expression. All the new variants were subjected to functional analysis to verify their pathogenic effects. This work underscores how the combination of different omics technologies and functional analysis can solve elusive cases in clinical practice.
Subject(s)
Maple Syrup Urine Disease , Metabolism, Inborn Errors , Infant, Newborn , Humans , Exome , Exome Sequencing , Metabolism, Inborn Errors/diagnosis , Metabolism, Inborn Errors/genetics , Neonatal ScreeningABSTRACT
We present the results of our experience in the diagnosis of inborn errors of metabolism (IEM) since the Expanded Newborn Screening was implemented in our Region. Dried blood samples were collected 48 h after birth. Amino acids and acylcarnitines were quantitated by mass spectrometry (MS)/MS. Newborns with alterations were referred to the clinical centers for follow-up. Biochemical and molecular genetic studies for confirmation of a disease were performed. In the period 2011 to 2019, 592 822 children were screened: 902 of them were referred for abnormal results. An IEM was confirmed in 222 (1/2670): aminoacidopathies: 89 hyperphenylalaninemia (HPA) (51 benign HPA, 32 phenylketonuria, 4 DNAJC12 defect, and 2 primapterinuria), 6 hypermethioninemia, 3 tyrosinemia type 1 (TYR-1), 1 TYR-3, 4 maple syrup urine disease (MSUD), 2 branched-chain amino acid transferase 2 deficiency, 2 homocystinuria, 1 cystinuria, 2 ornithine transcarbamylase (OTC) deficiency, 2 citrullinemia type I (CTLN1); FAO defects: 43 medium-chain acyl-CoA dehydrogenase deficiency (MCADD), 13 very long-chain acyl-CoA dehydrogenase deficiency, 2 long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), 1 multiple acyl-coA dehydrogenation deficiency, 11 systemic primary carnitine deficiency, 2 carnitine palmitoyltransferase type 2 (CPT-II) deficiency, 1 CPT-I deficiency; organic acidurias: 12 glutaric aciduria type 1 (GA-1), 4 methylmalonic acidemia (MMA), 7 MMA including combined cases with homocystinuria (MMAHC), 6 propionic acidemia (PA), 7 3-methylcrotonyl-CoA carboxylase, 1 3-hydroxy-3-methylglutaryl-CoA lyase deficiency lyase deficiency. Only 19 infants (8.5%) were symptomatic at newborn screening result (1 LCHADD, 5 PA, 1 CPT-II deficiency, 1 MMA, 3 MMAHC, 2 MSUD, 2 OTC deficiency, 1 CTLN1, 1 MCADD, 2 TYR-1). No false negative cases were identified. Genetic diagnosis was conclusive in all biochemically confirmed cases, except for two infants with HPA, identifying pathogenic variants in 32 different genes. The conditions with the highest incidence were HPA (1/6661) and MCAD deficiencies (1/13 787).
ABSTRACT
The eXtensible Markup Language (XML) files are widely used by the industry due to their flexibility in representing numerous kinds of data. Multiple applications such as financial records, social networks, and mobile networks use complex XML schemas with nested types, contents, and/or extension bases on existing complex elements or large real-world files. A great number of these files are generated each day and this has influenced the development of Big Data tools for their parsing and reporting, such as Apache Hive and Apache Spark. For these reasons, multiple studies have proposed new techniques and evaluated the processing of XML files with Big Data systems. However, a more usual approach in such works involves the simplest XML schemas, even though, real data sets are composed of complex schemas. Therefore, to shed light on complex XML schema processing for real-life applications with Big Data tools, we present an approach that combines three techniques. This comprises three main methods for parsing XML files: cataloging, deserialization, and positional explode. For cataloging, the elements of the XML schema are mapped into root, arrays, structures, values, and attributes. Based on these elements, the deserialization and positional explode are straightforwardly implemented. To demonstrate the validity of our proposal, we develop a case study by implementing a test environment to illustrate the methods using real data sets provided from performance management of two mobile network vendors. Our main results state the validity of the proposed method for different versions of Apache Hive and Apache Spark, obtain the query execution times for Apache Hive internal and external tables and Apache Spark data frames, and compare the query performance in Apache Hive with that of Apache Spark. Another contribution made is a case study in which a novel solution is proposed for data analysis in the performance management systems of mobile networks.
ABSTRACT
BACKGROUND: The COVID-19 lockdown has had a significant impact on mental health. Patients with eating disorders (ED) have been particularly vulnerable. AIMS: (1) To explore changes in eating-related symptoms and general psychopathology during lockdown in patients with an ED from various European and Asian countries; and (2) to assess differences related to diagnostic ED subtypes, age, and geography. METHODS: The sample comprised 829 participants, diagnosed with an ED according to DSM-5 criteria from specialized ED units in Europe and Asia. Participants were assessed using the COVID-19 Isolation Scale (CIES). RESULTS: Patients with binge eating disorder (BED) experienced the highest impact on weight and ED symptoms in comparison with other ED subtypes during lockdown, whereas individuals with other specified feeding and eating disorders (OFSED) had greater deterioration in general psychological functioning than subjects with other ED subtypes. Finally, Asian and younger individuals appeared to be more resilient. CONCLUSIONS: The psychopathological changes in ED patients during the COVID-19 lockdown varied by cultural context and individual variation in age and ED diagnosis. Clinical services may need to target preventive measures and adapt therapeutic approaches for the most vulnerable patients.
Subject(s)
COVID-19/prevention & control , COVID-19/psychology , Feeding and Eating Disorders/psychology , Quarantine/psychology , Social Isolation/psychology , Adolescent , Adult , Asia , Child , Europe , Female , Humans , Internationality , Longitudinal Studies , Male , SARS-CoV-2 , Young AdultABSTRACT
Biallelic variants of the gene DNAJC12, which encodes a cochaperone, were recently described in patients with hyperphenylalaninemia (HPA). This paper reports the retrospective genetic analysis of a cohort of unsolved cases of HPA. Biallelic variants of DNAJC12 were identified in 20 patients (generally neurologically asymptomatic) previously diagnosed with phenylalanine hydroxylase (PAH) deficiency (phenylketonuria [PKU]). Further, mutations of DNAJC12 were identified in four carriers of a pathogenic variant of PAH. The genetic spectrum of DNAJC12 in the present patients included four new variants, two intronic changes c.298-2A>C and c.502+1G>C, presumably affecting the splicing process, and two exonic changes c.309G>T (p.Trp103Cys) and c.524G>A (p.Trp175Ter), classified as variants of unknown clinical significance (VUS). The variant p.Trp175Ter was detected in 83% of the mutant alleles, with 14 cases homozygous, and was present in 0.3% of a Spanish control population. Functional analysis indicated a significant reduction in PAH and its activity, reduced tyrosine hydroxylase stability, but no effect on tryptophan hydroxylase 2 stability, classifying the two VUS as pathogenic variants. Additionally, the effect of the overexpression of DNAJC12 on some destabilizing PAH mutations was examined and a mutation-specific effect on stabilization was detected suggesting that the proteostasis network could be a genetic modifier of PAH deficiency and a potential target for developing mutation-specific treatments for PKU.
Subject(s)
Phenylketonurias/genetics , Repressor Proteins/genetics , Adolescent , Adult , Alleles , Child , Child, Preschool , DNA Mutational Analysis , Exons , Humans , Infant , Infant, Newborn , Introns , RNA Splicing , Retrospective Studies , SpainABSTRACT
Congenital lactic acidosis (CLA) is a rare condition in most instances due to a range of inborn errors of metabolism that result in defective mitochondrial function. Even though the implementation of next generation sequencing has been rapid, the diagnosis rate for this highly heterogeneous allelic condition remains low. The present work reports our group's experience of using a clinical/biochemical analysis system in conjunction with genetic findings that facilitates the taking of timely clinical decisions with minimum need for invasive procedures. The system's workflow combines different metabolomics datasets and phenotypic information with the results of clinical exome sequencing and/or RNA analysis. The system's use detected genetic variants in 64% of a cohort of 39 CLA-patients; these variants, 14 of which were novel, were found in 19 different nuclear and two mitochondrial genes. For patients with variants of unknown significance, the genetic analysis was combined with functional genetic and/or bioenergetics analyses in an attempt to detect pathogenicity. Our results warranted subsequent testing of antisense therapy to rescue the abnormal splicing in cultures of fibroblasts from a patient with a defective GFM1 gene. The discussed system facilitates the diagnosis of CLA by avoiding the need to use invasive techniques and increase our knowledge of the causes of this condition.
ABSTRACT
A human induced pluripotent stem cell (iPSC) line was generated from fibroblasts of a patient with propionic acidemia that has a homozygous mutation (c.1218_1231del14ins12 (p.G407â¯fs)) in the PCCB gene. Reprogramming factors OCT3/4, SOX2, KLF4 and c-MYC were delivered using a non-integrative method based on the Sendai virus. Once established, iPSCs have shown full pluripotency, differentiation capacity and genetic stability. The generated iPSC line represents a useful tool to study the pathomechanisms underlying the deficiency.
Subject(s)
Homozygote , Induced Pluripotent Stem Cells , Methylmalonyl-CoA Decarboxylase , Mutation , Propionic Acidemia , Cell Line , Humans , Induced Pluripotent Stem Cells/enzymology , Induced Pluripotent Stem Cells/pathology , Kruppel-Like Factor 4 , Methylmalonyl-CoA Decarboxylase/genetics , Methylmalonyl-CoA Decarboxylase/metabolism , Propionic Acidemia/enzymology , Propionic Acidemia/genetics , Propionic Acidemia/pathologyABSTRACT
The congenital disorders of glycosylation (CDG) are defects in glycoprotein and glycolipid glycan synthesis and attachment. They affect multiple organ/systems, but non-specific symptoms render the diagnosis of the different CDG very challenging. Phosphomannomutase 2 (PMM2)-CDG is the most common CDG, but advances in genetic analysis have shown others to occur more commonly than previously thought. The present work reports the clinical and mutational spectrum of 25 non-PMM2 CDG patients. The most common clinical symptoms were hypotonia (80%), motor or psychomotor disability (80%) and craniofacial dysmorphism (76%). Based on their serum transferrin isoform profile, 18 were classified as CDG-I and 7 as CDG-II. Pathogenic variations were found in 16 genes (ALG1, ALG6, ATP6V0A2, B4GALT1, CCDC115, COG7, DOLK, DPAGT1, DPM1, GFPT1, MPI, PGM1, RFT1, SLC35A2, SRD5A3, and SSR4). Overall, 27 variants were identified, 12 of which are novel. The results highlight the importance of combining genetic and biochemical analyses for the early diagnosis of this heterogeneous group of disorders.
Subject(s)
Congenital Disorders of Glycosylation/diagnosis , Congenital Disorders of Glycosylation/genetics , Phosphotransferases (Phosphomutases)/genetics , Adolescent , Adult , Child , Child, Preschool , Female , Humans , Infant , Male , SpainABSTRACT
The present work describes the value of genetic analysis as a confirmatory measure following the detection of suspected inborn errors of metabolism in the Spanish newborn mass spectrometry screening program. One hundred and forty-one consecutive DNA samples were analyzed by next-generation sequencing using a customized exome sequencing panel. When required, the Illumina extended clinical exome panel was used, as was Sanger sequencing or transcriptional profiling. Biochemical tests were used to confirm the results of the genetic analysis. Using the customized panel, the metabolic disease suspected in 83 newborns (59%) was confirmed. In three further cases, two monoallelic variants were detected for two genes involved in the same biochemical pathway. In the remainder, either a single variant or no variant was identified. Given the persistent absence of biochemical alterations, carrier status was assigned in 39 cases. False positives were recorded for 11. In five cases in which the biochemical pattern was persistently altered, further genetic analysis allowed the detection of two variants affecting the function of BCAT2, ACSF3, and DNAJC12, as well as a second, deep intronic variant in ETFDH or PTS. The present results suggest that genetic analysis using extended next-generation sequencing panels can be used as a confirmatory test for suspected inborn errors of metabolism detected in newborn screening programs. Biochemical tests can be very helpful when a diagnosis is unclear. In summary, simultaneous genomic and metabolomic analyses can increase the number of inborn errors of metabolism that can be confirmed following suggestive newborn screening results.
Subject(s)
Genetic Testing , Lipid Metabolism, Inborn Errors/genetics , Metabolism, Inborn Errors/genetics , Neonatal Screening , Exome/genetics , High-Throughput Nucleotide Sequencing , Humans , Infant, Newborn , Lipid Metabolism, Inborn Errors/diagnosis , Lipid Metabolism, Inborn Errors/epidemiology , Metabolism, Inborn Errors/diagnosis , Metabolism, Inborn Errors/epidemiology , Mutation/genetics , Spain/epidemiology , Exome SequencingABSTRACT
Se presenta la vida y obra de la Dra. Ada Carmen Ovies García, figura relevante de la Ginecología y la Obstetricia tanto en nuestro país como en el mundo, haciéndose énfasis en su labor docente, asistencial y directiva dentro del Sistema Nacional de Salud (AU)
Subject(s)
Humans , Female , Gynecology/history , Obstetrics/history , Faculty/historyABSTRACT
Propionic acidemia (PA) is caused by mutations in the PCCA and PCCB genes, encoding α and ß subunits, respectively, of the mitochondrial enzyme propionyl-CoA carboxylase (PCC). Up to date, >200 pathogenic mutations have been identified, mostly missense defects. Genetic analysis in PA patients referred to the laboratory for the past 15â¯years identified 20 novel variants in the PCCA gene and 14 in the PCCB gene. 21 missense variants were predicted as probably disease-causing by different bioinformatics algorithms. Structural analysis in the available 3D model of the PCC enzyme indicated potential instability for most of them. Functional analysis in a eukaryotic system confirmed the pathogenic effect for the missense variants and for one amino acid deletion, as they all exhibited reduced or null PCC activity and protein levels compared to wild-type constructs. PCCB variants p.E168del, p.Q58P and p.I460T resulted in medium-high protein levels and no activity. Variants p.R230C and p.C712S in PCCA, and p.G188A, p.R272W and p.H534R in PCCB retained both partial PCC activity and medium-high protein levels. Available patients-derived fibroblasts carriers of some of these mutations were grown at 28⯰C or 37⯰C and a slight increase in PCC activity or protein could be detected in some cases at the folding-permissive conditions. Examination of available clinical data showed correlation of the results of the functional analysis with disease severity for most mutations, with some notable exceptions, confirming the notion that the final phenotypic outcome in PA is not easily predicted.
Subject(s)
Genetic Predisposition to Disease , Methylmalonyl-CoA Decarboxylase/genetics , Propionic Acidemia/genetics , Structure-Activity Relationship , Adolescent , Adult , Child , Child, Preschool , Female , Genetic Association Studies , Genotype , Humans , Infant , Infant, Newborn , Male , Methylmalonyl-CoA Decarboxylase/chemistry , Mitochondria/enzymology , Mitochondria/genetics , Mutation, Missense/genetics , Neonatal Screening , Propionic Acidemia/pathology , Protein Conformation , Protein Folding , Young AdultABSTRACT
BACKGROUND: Cellular cobalamin defects are a locus and allelic heterogeneous disorder. The gold standard for coming to genetic diagnoses of cobalamin defects has for some time been gene-by-gene Sanger sequencing of individual DNA fragments. Enzymatic and cellular methods are employed before such sequencing to help in the selection of the gene defects to be sought, but this is time-consuming and laborious. Furthermore some cases remain undiagnosed because no biochemical methods have been available to test for cobalamin absorption and transport defects. RESULTS: This paper reports the use of massive parallel sequencing of DNA (exome analysis) for the accurate and rapid genetic diagnosis of cobalamin-related defects in a cohort of affected patients. The method was first validated in an initial cohort with different cobalamin defects. Mendelian segregation, the frequency of mutations, and the comprehensive structural and functional analysis of gene variants, identified disease-causing mutations in 12 genes involved in the absorption and synthesis of active cofactors of vitamin B12 (22 cases), and in the non-cobalamin metabolism-related genes ACSF3 (in four biochemically misdiagnosed patients) and SUCLA2 (in one patient with an unusual presentation). We have identified thirteen new variants all classified as pathogenic according to the ACGM recommendation but four were classified as variant likely pathogenic in MUT and SUCLA2. Functional and structural analysis provided evidences to classify them as pathogenic variants. CONCLUSIONS: The present findings suggest that the technology used is sufficiently sensitive and specific, and the results it provides sufficiently reproducible, to recommend its use as a second-tier test after the biochemical detection of cobalamin disorder markers in the first days of life. However, for accurate diagnoses to be made, biochemical and functional tests that allow comprehensive clinical phenotyping are also needed.
Subject(s)
Amino Acid Metabolism, Inborn Errors/genetics , Homocystinuria/genetics , Vitamin B 12 Deficiency/genetics , Coenzyme A Ligases/genetics , Female , High-Throughput Nucleotide Sequencing , Humans , Male , Mutation/genetics , Succinate-CoA Ligases/genetics , Vitamin B 12/metabolism , Vitamin B 12 Deficiency/metabolismABSTRACT
Human induced pluripotent stem cell (iPSC) line was generated from fibroblasts of a patient with propionic acidemia carrying mutations in the PCCA gene: c.1899+4_1899+7delAGTA; p.(Cys616_Val633del) and c.1430--?_1643+?del; p.(Gly477Glufs*9). Reprogramming factors OCT3/4, SOX2, KLF4 and c-MYC were delivered using a non-integrative method based on the Sendai virus. Once established, iPSCs have shown full pluripotency, differentiation capacity and genetic stability.
Subject(s)
Cell Culture Techniques/methods , Induced Pluripotent Stem Cells/pathology , Methylmalonyl-CoA Decarboxylase/genetics , Propionic Acidemia/pathology , Base Sequence , Cell Line , Humans , Kruppel-Like Factor 4 , Reproducibility of ResultsABSTRACT
En el 2011 la Facultad de Ciencias Médicas de Mayabeque no contaba con conexión a la red Infomed y a solicitud del departamento de Historia y Filosofía se diseñó una página web estática.Objetivo: Valorar la efectividad de la página web estática Historia de la Salud en Mayabeque a partir del uso que han hecho los usuarios de la red de bibliotecas.Método: Se realizó un estudio descriptivo de corte transversal en la red de bibliotecas de la provincia en el periodo comprendido desde septiembre del 2011 a julio del 2015. El universo estuvo constituido por los usuarios que acudieron a las 26 unidades de la red en la provincia y utilizaron la página, de las que se tomó una muestra intencional de 15 bibliotecas docentes y aleatoria de 281 usuarios.Resultados: Se operó con las variables: uso de la página, categoría de usuario, sexo y edad. Los indicadores para determinar la efectividad de la página fueron: para qué se ha usado la página y evaluación del usuario a partir de una escala de 1 a 5.Discusión: Son los estudiantes del sexo femenino los que más usan la página. Se evidencia el poco uso que hacen los profesores. La página web es efectiva atendiendo al uso realizado por sus usuarios, contribuye a su alfabetización informacional y constituye un medio de apoyo a la enseñanza(AU)
The Faculty of Medical Sciences in Mayabeque province didn't have an Infomed network connection back in 2011, therefore, as a request of the History and Philosophy Department, a static web page was designed.Objective: assessing the effectiveness of the Health History in Mayabeque static web page starting from how libraries network users have made use of it.Method: A cross section descriptive study of the libraries network was made in the province from September 2011 to July 2015. The population consisted of users who went to the 26 libraries in the province to use the page. An intentional sample of 15 teaching libraries and a random sample of 281 users was taken.Results: The following variables were taken into account: web page use, user category, sex and age. In order to determine the effectiveness of the page, the subsequent indicators were used: "what was the page used for" and assessment of the user from a 1 to 5 scale.Discussion: Female students use the page the most. The study showed professors make little use of it. The web page is effective according to the use users make of it; it contributes to their information literacy and it is a teaching aid(AU)
Subject(s)
Humans , Webcasts as Topic , Social Media , Public Health/history , Epidemiology, Descriptive , Cross-Sectional StudiesABSTRACT
En el 2011 la Facultad de Ciencias Médicas de Mayabeque no contaba con conexión a la red Infomed y a solicitud del departamento de Historia y Filosofía se diseñó una página web estática. Objetivo: Valorar la efectividad de la página web estática Historia de la Salud en Mayabeque a partir del uso que han hecho los usuarios de la red de bibliotecas. Método: Se realizó un estudio descriptivo de corte transversal en la red de bibliotecas de la provincia en el periodo comprendido desde septiembre del 2011 a julio del 2015. El universo estuvo constituido por los usuarios que acudieron a las 26 unidades de la red en la provincia y utilizaron la página, de las que se tomó una muestra intencional de 15 bibliotecas docentes y aleatoria de 281 usuarios. Resultados: Se operó con las variables: uso de la página, categoría de usuario, sexo y edad. Los indicadores para determinar la efectividad de la página fueron: para qué se ha usado la página y evaluación del usuario a partir de una escala de 1 a 5. Discusión: Son los estudiantes del sexo femenino los que más usan la página. Se evidencia el poco uso que hacen los profesores. La página web es efectiva atendiendo al uso realizado por sus usuarios, contribuye a su alfabetización informacional y constituye un medio de apoyo a la enseñanza.
The Faculty of Medical Sciences in Mayabeque province didn't have an Infomed network connection back in 2011, therefore, as a request of the History and Philosophy Department, a static web page was designed. Objective: assessing the effectiveness of the Health History in Mayabeque static web page starting from how libraries network users have made use of it. Method: A cross section descriptive study of the libraries network was made in the province from September 2011 to July 2015. The population consisted of users who went to the 26 libraries in the province to use the page. An intentional sample of 15 teaching libraries and a random sample of 281 users was taken. Results: The following variables were taken into account: web page use, user category, sex and age. In order to determine the effectiveness of the page, the subsequent indicators were used: "what was the page used for" and assessment of the user from a 1 to 5 scale. Discussion: Female students use the page the most. The study showed professors make little use of it. The web page is effective according to the use users make of it; it contributes to their information literacy and it is a teaching aid.
ABSTRACT
The rapid analysis of genomic data is providing effective mutational confirmation in patients with clinical and biochemical hallmarks of a specific disease. This is the case for nonketotic hyperglycinemia (NKH), a Mendelian disorder causing seizures in neonates and early-infants, primarily due to mutations in the GLDC gene. However, understanding the impact of missense variants identified in this gene is a major challenge for the application of genomics into clinical practice. Herein, a comprehensive functional and structural analysis of 19 GLDC missense variants identified in a cohort of 26 NKH patients was performed. Mutant cDNA constructs were expressed in COS7 cells followed by enzymatic assays and Western blot analysis of the GCS P-protein to assess the residual activity and mutant protein stability. Structural analysis, based on molecular modeling of the 3D structure of GCS P-protein, was also performed. We identify hypomorphic variants that produce attenuated phenotypes with improved prognosis of the disease. Structural analysis allows us to interpret the effects of mutations on protein stability and catalytic activity, providing molecular evidence for clinical outcome and disease severity. Moreover, we identify an important number of mutants whose loss-of-functionality is associated with instability and, thus, are potential targets for rescue using folding therapeutic approaches.