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This study investigates the role of all-trans retinoic acid (ATRA) in modulating the expression of heat shock protein 90 (Hsp90) and its influence on the uptake and degradation of tau proteins in immortalized human microglia cells. We demonstrate that ATRA significantly upregulates Hsp90 expression in a concentration-dependent manner, enhancing both extracellular and intracellular Hsp90 levels. Our results show that ATRA-treated cells exhibit increased tau protein uptake via caveolae/raft-dependent endocytosis pathways. This uptake is mediated by surface Hsp90, as evidenced by the inhibition of tau internalization using an extracellular Hsp90-selective inhibitor. Further, we establish that the exogenously added full-sized monomeric tau proteins bind to Hsp90. The study also reveals that ATRA-enhanced tau uptake is followed by effective degradation through both lysosomal and proteasomal pathways. We observed a significant reduction in intracellular tau levels in ATRA-treated cells, which was reversed by lysosome or proteasome inhibitors, suggesting the involvement of both degradation pathways. Our findings highlight the potential therapeutic role of ATRA in Alzheimer's disease and related tauopathies. By enhancing Hsp90 expression and facilitating tau degradation, ATRA could contribute to the clearance of pathological tau proteins, offering a promising strategy for mitigating neurodegeneration. This research underscores the need for further exploration into the molecular mechanisms of tau protein internalization and degradation, which could provide valuable insights into the treatment of neurodegenerative diseases.
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We aimed to determine the role of cathepsin S (CTSS) in modulating oxidative stress-induced immune and inflammatory reactions and angiogenesis in age-related macular degeneration. Human retinal pigment epithelium cells line ARPE-19 (immature) were maintained and treated with H2O2. The expression of CTSS, inflammatory cytokines, and complement factors induced by oxidative stress was compared between cells incubated without (control) and with CTSS knockdown (using small interfering ribonucleic acid; siRNA). To evaluate the role of CTSS in angiogenesis, we assayed tube formation using human umbilical vein endothelial cells and conditioned medium from ARPE-19 cells. We also used a mouse model of laser-induced choroidal neovascularization. CTSS levels were higher in ARPE-19 cells treated with H2O2 than in control cells. Oxidative stress-induced CTSS resulted in significantly elevated transcription of nuclear factor kappa B-dependent inflammatory cytokines, complement factors C3a and C5a, membrane attack complex (C5b-9), and C3a and C5a receptors. siRNA-mediated knockdown of CTSS reduced the number of inflammatory signals. Furthermore, oxidative stress-induced CTSS regulated the expression of peroxisome proliferator-activated receptor γ and vascular endothelial growth factor A/Akt serine/threonine kinase family signaling, which led to angiogenesis. Tube formation assays and mouse models of choroidal neovascularization revealed that CTSS knockdown ameliorated angiogenesis in vitro and in vivo. The present findings suggest that CTSS modulates the complement pathway, inflammatory reactions, and neovascularization, and that CTSS knockdown induces potent immunomodulatory effects. Hence, it could be a promising target for the prevention and treatment of early- and late-stage age-related macular degeneration.
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Catepsinas , Neovascularização de Coroide , Modelos Animais de Doenças , Degeneração Macular , Estresse Oxidativo , Epitélio Pigmentado da Retina , Humanos , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia , Animais , Camundongos , Neovascularização de Coroide/metabolismo , Neovascularização de Coroide/genética , Neovascularização de Coroide/patologia , Catepsinas/metabolismo , Catepsinas/genética , Degeneração Macular/metabolismo , Degeneração Macular/genética , Degeneração Macular/patologia , Camundongos Endogâmicos C57BL , Western Blotting , Linhagem Celular , Citocinas/metabolismo , RNA Interferente Pequeno/genética , Células Endoteliais da Veia Umbilical Humana/metabolismoRESUMO
Talaromyces sp. DC2 is an endophytic fungus that was isolated from the stem of Catharanthus roseus (L.) G. Don in Hanoi, Vietnam and is capable of producing vinca alkaloids. This study utilizes the PacBio Sequel technology to completely sequence the whole genome of Talaromyces sp. DC2The genome study revealed that DC2 contains a total of 34.58 Mb spanned by 156 contigs, with a GC content of 46.5%. The identification and prediction of functional protein-coding genes, tRNA, and rRNA were comprehensively predicted and highly annotated using various BLAST databases, including non-redundant (Nr) protein sequence, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Clusters of Orthologous Groups (COG), and Carbohydrate-Active Enzymes (CAZy) databases. The genome of DC2 has a total of 149, 227, 65, 153, 53, and 6 genes responsible for cellulose, hemicellulose, lignin, pectin, chitin, starch, and inulin degradation, respectively. The Antibiotics and Secondary Metabolites Analysis Shell (AntiSMASH) analyses revealed that strain DC2 possesses 20 biosynthetic gene clusters responsible for producing secondary metabolites. The strain DC2 has also been found to harbor the DDC gene encoding aromatic L-amino acid decarboxylase enzyme. Conclusively, this study has provided a comprehensive understanding of the processes involved in secondary metabolites and the ability of the Talaromyces sp. DC2 strain to degrade plant cell walls.
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In this study, strain DM10 was isolated from mangrove roots and characterized as a halotolerant plant growth-promoting bacterium. Strain DM10 exhibited the ability to solubilize phosphate, produce siderophore, show 1-aminocyclopropane-1-carboxylic acid deaminase activity, and hydrolyze starch. The rice plants subjected to a treatment of NaCl (200 mM) and inoculated with strain DM10 showed an improvement in the shoot length, root length, and dried weight, when compared to those exposed solely to saline treatment. The comprehensive genome sequencing of strain DM10 revealed a genome spanning of 4,171,745 bp, harboring 3626 protein coding sequences. Within its genome, strain DM10 possesses genes responsible for both salt-in and salt-out strategies, indicative of a robust genetic adaptation aimed at fostering salt tolerance. Additionally, the genome encodes genes involved in phosphate solubilization, such as the synthesis of gluconic acid, high-affinity phosphate transport systems, and alkaline phosphatase. In the genome of DM10, we identified the acdS gene, responsible for encoding 1-aminocyclopropane-1-carboxylate deaminase, as well as the amy1A gene, which encodes α-amylase. Furthermore, the genome of DM10 contains sequences associated with the iron (3+)-hydroxamate and iron uptake clusters, responsible for siderophore production. Such data provide a deep understanding of the mechanism employed by strain DM10 to combat osmotic and salinity stress, facilitate plant growth, and elucidate its molecular-level behaviors.
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BACKGROUND/AIM: Although the expression of mucin 1(MUC1) and prostate stem cell antigen (PSCA) genes is correlated with gastric cancer development and progression, the utility of these two genes as biomarkers of gastric cancer prognosis still needs to be confirmed in clinical practice. This study aimed to develop a model predictive of gastric cancer that integrates several significant single nucleotide polymorphisms (SNPs) of MUC1 and PSCA genes, and some health-risk behavior factors in a Vietnamese population. PATIENTS AND METHODS: A total of 302 patients with primary gastric carcinoma and 304 healthy persons were included in a case-control study. The generalized linear model was used with the profile of age, sex, history of smoking and using alcohol, personal and family medical history of stomach diseases, and the SNPs of MUC1 and PSCA. The prognostic value of the model was assessed by the area under a receiver operating characteristic curve (AUC) and Akaike Information Criterion (AIC) values. RESULTS: In male participants, the final model, consisting of age, sex, history of smoking and using alcohol, personal and family medical history of stomach diseases and SNP MUC1 rs4072037, provided acceptable discrimination, with an AUC of 0.6374 and the lowest AIC value (539.53). In female participants, the predictive model including age, sex, history of smoking and using alcohol, personal and family medical history of stomach diseases, SNPs MUC1 rs4072037 and rs2070803 had an AUC of 0.6937 and AIC of 266.80. The calibration plots of the male model approximately fitted the ideal calibration line. CONCLUSION: The predictive model based on age, sex, medical history, and genetic and health-risk behavior factors has a high potential in determining gastric cancer. Further studies that elucidate other genetic variants should be carried out to define high-risk gastric cancer groups and propose appropriate personalized prevention.
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Neoplasias Gástricas , Humanos , Masculino , Feminino , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Predisposição Genética para Doença , Mucina-1/genética , Estudos de Casos e Controles , População do Sudeste Asiático , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Assunção de Riscos , Fatores de RiscoRESUMO
Background: Merosin-deficient congenital muscular dystrophy type 1A (MDC1A), also known as laminin-α2 chain-deficient congenital muscular dystrophy (LAMA2-MD), is an autosomal recessive disease caused by biallelic variants in the LAMA2 gene. In MDC1A, laminin- α2 chain expression is absent or significantly reduced, leading to some early-onset clinical symptoms including severe hypotonia, muscle weakness, skeletal deformity, non-ambulation, and respiratory insufficiency. Methods: Six patients from five unrelated Vietnamese families presenting with congenital muscular dystrophy were investigated. Targeted sequencing was performed in the five probands. Sanger sequencing was carried out in their families. Multiplex ligation-dependent probe amplification was performed in one family to examine an exon deletion. Results: Seven variants of the LAMA2 (NM_000426) gene were identified and classified as pathogenic/likely pathogenic variants using American College of Medical Genetics and Genomics criteria. Two of these variants were not reported in the literature, including c.7156-5_7157delinsT and c.8974_8975insTGAT. Sanger sequencing indicated their parents as carriers. The mothers of family 4 and family 5 were pregnant and a prenatal testing was performed. The results showed that the fetus of the family 4 only carries c.4717 + 5G>A in the heterozygous form, while the fetus of the family 5 carries compound heterozygous variants, including a deletion of exon 3 and c.4644C>A. Conclusion: Our findings not only identified the underlying genetic etiology for the patients, but also provided genetic counseling for the parents whenever they have an offspring.
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Rice is the second-most important primary crop in the world and one of the most susceptible crops to salt stress. Soil salinization hinders seedling growth and decreases crop yield by inducing ionic and osmotic imbalances, photosynthesis disturbances, cell wall alterations, and gene expression inhibition. Plants have developed a range of defense mechanisms to adapt to salt stress. One of the most effective means is to make use of plant microRNAs (miRNAs) as post-transcriptional regulators to regulate the expression of developmental genes in order to mitigate the detrimental effects of salt stress. In this study, the miRNA sequencing data between two contrasting rice cultivars, salt-tolerant Doc Phung (DP) and salt-sensitive IR28 seedlings, were compared under control and salt stress (150 mM NaCl) conditions to determine the salt stress-responsive miRNAs. Comparative analysis of miRNA sequencing data detected a total of 69 differentially expressed miRNAs in response to salt stress treatment. Among them, 18 miRNAs from 13 gene families, MIR156, MIR164, MIR167, MIR168, MIR171, MIR396, MIR398, MIR1432, MIR1846, MIR1857, MIR1861, MIR3979, and MIR5508, were identified to be specifically and significantly expressed in the shoot and root tissues of DP seedlings. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses further revealed that these detected miRNAs regulate a range of essential biological and stress response processes, including gene transcription, osmotic homeostasis, root formation, ROS scavenger synthesis, and auxin and abscisic acid signaling pathways. Our findings provide more insight into the miRNA-mediated responsive mechanisms of rice under salt stress and should benefit the improvement of salt stress tolerance in rice.
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MicroRNAs , Oryza , Oryza/genética , Regulação da Expressão Gênica de Plantas , MicroRNAs/genética , Plantas Geneticamente Modificadas , Estresse Salino/genéticaRESUMO
Multisystem inflammatory syndrome is associated with COVID-19 and can result in reduced food intake, increased muscle catabolism, and electrolyte imbalance. Therefore COVID-19 patients are at high risk of being malnourished and of refeeding syndrome. The present study aimed to determine the prevalence and correlates of malnutrition and refeeding syndrome (RS) among COVID-19 patients in Hanoi, Vietnam. This prospective cohort study analyzed data from 1207 patients who were treated at the COVID-19 hospital of Hanoi Medical University (HMUH COVID-19) between September 2021 and March 2022. Nutritional status was evaluated by the Global Leadership Initiative on Malnutrition (GLIM) and laboratory markers. GLIM-defined malnutrition was found in 614 (50.9%) patients. Among those with malnutrition, 380 (31.5%) and 234 (19.4%) had moderate and severe malnutrition, respectively. The prevalence of risk of RS was 346 (28.7%). Those with severe and critical COVID symptoms are more likely to be at risk of RS compared to those with mild or moderate COVID, and having severe and critical COVID-19 infection increased the incidence of RS by 2.47 times, compared to mild and moderate disease. There was an association between levels of COVID-19, older ages, comorbidities, the inability of eating independently, hypoalbuminemia and hyponatremia with malnutrition. The proportion of COVID-19 patients who suffered from malnutrition was high. These results underscore the importance of early nutritional screening and assessment in COVID-19 patients, especially those with severe and critical infection.
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COVID-19 , Desnutrição , Síndrome da Realimentação , Humanos , Estado Nutricional , Síndrome da Realimentação/epidemiologia , Vietnã/epidemiologia , Avaliação Nutricional , Estudos Prospectivos , COVID-19/epidemiologia , Desnutrição/epidemiologia , HospitaisRESUMO
Viet Nam has a coastline of 3200 km with thousands of islands providing diverse habitats for benthic harmful algal species including species of Gambierdiscus. Some of these species produce ciguatera toxins, which may accumulate in large carnivore fish potentially posing major threats to public health. This study reports five species of Gambierdiscus from Vietnamese waters, notably G. australes, G. caribaeus, G. carpenteri, G. pacificus, and G. vietnamensis sp. nov. All species are identified morphologically by LM and SEM, and identifications are supported by molecular analyses of nuclear rDNA (D1-D3 and D8-D10 domains of LSU, SSU, and ITS1-5.8S-ITS2 region) based on cultured material collected during 2010-2021. Statistical analyses of morphometric measurements may be used to differentiate some species if a sufficiently large number of cells are examined. Gambierdiscus vietnamensis sp. nov. is morphologically similar to other strongly reticulated species, such as G. belizeanus and possibly G. pacificus; the latter species is morphologically indistinguishable from G. vietnamensis sp. nov., but they are genetically distinct, and molecular analysis is deemed necessary for proper identification of the new species. This study also revealed that strains denoted G. pacificus from Hainan Island (China) should be included in G. vietnamensis sp. nov.
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Ciguatera , Dinoflagellida , Animais , Dinoflagellida/genética , DNA Ribossômico/genética , Filogenia , VietnãRESUMO
Marinobacter sp. strain C7 was isolated from seawater collected on the Con Bung coast, Vietnam. Here, we report a draft genome sequence of strain C7 consisting of 4,057,300 bp with 59.2% GC content and 109 contigs. The genome sequence of strain C7 provides an overview of its halophilic properties.
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Chloroaluminate ionic liquid bound on magnetic nanoparticles (Fe3O4@O2Si[PrMIM]Cl·AlCl3) was prepared and used as a heterogenous Lewis acidic catalyst for the Friedel-Crafts sulfonylation of aromatic compounds with sulfonyl chlorides or p-toluenesulfonic anhydride. The catalyst's stability, efficiency, easy recovery, and high recyclability without considerable loss of catalytic capability after four recycles were evidence of its advantages. Furthermore, the stoichiometry, wide substrate scope, short reaction time, high yield of sulfones, and solvent-free reaction condition also made this procedure practical, ecofriendly, and economical.
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BACKGROUND: A few studies revealed that the polymorphisms of Mucin 1 gene have a role and significance as a susceptible factor contributing to gastric cancer. To better understand the roles of two MUC1 genotype polymorphisms of rs4072037 and rs2070803 in the development of gastric cancer in Vietnamese population, a multicenter, large-sample, case-control study was conducted to investigate the potential association of these single-nucleotide polymorphisms (SNPs) of MUC1 gene with gastric cancer risk and to evaluate the combination factors in relation with these SNPs. METHODS: This case-control study included 302 gastric cancer patients and 304 controls at four national medical hospitals between 2016 and 2018. All participants were interviewed for sociodemographic characteristics, smoking and drinking status, and personal and family history of gastric diseases. Genotyping was done using polymerase chain reaction-restriction fragment length polymorphism analysis. The association of SNPs with gastric cancer was explored using logistic regression models. RESULTS: AA genotype for rs4072037 was significantly associated with increased gastric cancer. Those with AA genotype had higher gastric cancer risk than had patients with AG (OR: 2.09, 95% CI: 1.48-2.96) and a combination of AG+GG (OR: 1.85, 95% CI: 1.33-2.56). In rs2070803, GG genotype increased gastric cancer risk when compared with AG (OR: 1.97, 95% CI: 1.39-2.80) and AG+AA (OR: 1.71, 95% CI: 1.23-2.39). AG genotypes in both SNPs decreased gastric cancer risk when compared with homogenous genotype, more specifically AA (OR: 0.51, 95% CI: 0.35-0.72) and GG (OR: 0.58, 95% CI: 0.35-0.97). These genotypes in combination with above-60-year-old age, male gender, alcoholism, and personal history of gastric disease were also significantly elevated risk factors for gastric cancer. CONCLUSIONS: rs4072037 and rs2070803 of Mucin 1 genes are two genotypic risk factors for gastric cancer. Those in combination with gender, family history, smoking, and drinking habits significantly increase the risk of gastric cancer.
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The nitroxide spin label is the most widely used probe for electron paramagnetic resonance (EPR) spectroscopy studies of the structure and function of biomolecules. However, the role of surrounding environments in determining the dynamics of nitroxide spin labels in biological complex systems remains to be clarified. This study aims to characterize the dynamics and environmental structure of spin labels in the voltage-sensing domain (VSD) of a KvAP potassium channel by means of molecular dynamics (MD) studies. MD simulations for unlabeled and 132 spin-labeled KvAP-VSD models (spin labels introduced at positions 20-151) were carried out in a phospholipid bilayer to evaluate conformational dynamics of nitroxide spin-label side chains in the VSD. Structural flexibility, conformational freedom, and orientation of the spin-label side chains were investigated in relation to their dynamics in different microenvironments. The analysis of MD data showed that the attached spin-label probe did not severely perturb the protein dynamics. The conformational freedoms of the nitroxide side chain vary with the physical structure of the surrounding environments. The two terminal dihedral angles of the nitroxide side chain tend to cluster and adopt several preferred rotameric states. From the nearest-neighbor analysis, the spin label can be exposed to either a homogeneous or heterogeneous environment with various exposure scenarios. The dynamical movement of KvAP-VSD is high at a water-exposed site, moderate in the membrane, and low in the protein core. Understanding the structure and dynamics behaviors of spin labels helps to manage the experimental uncertainty and avoid misleading interpretation in relation to the protein structure.
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Simulação de Dinâmica Molecular , Proteínas , Espectroscopia de Ressonância de Spin Eletrônica , Conformação Molecular , Marcadores de SpinRESUMO
BACKGROUND: Primordial dwarfism (PD) is a group of genetically heterogeneous disorders related to developmental disabilities occurring in the uterus and prolongs during all stages of life, resulting in short stature, facial deformities and abnormal brain. OBJECTIVE: To determine the exact cause of the disease in two Vietnamese patients priory diagnosed with PD by severe pre-and postnatal growth retardation with marked microcephaly and some bone abnormalities. METHODS: Whole-exome sequencing was performed for the two patients and mutations in genes related to PD were screened. Sanger sequencing was applied to examine the mutations in the patients of their families. RESULTS: Three novel mutations in the PCNT gene which have not been reported previously were identified in the two patients. Of which, two frameshift mutations (p.Thr479Profs*6 and p.Glu2742Alafs*8) were detected in patient I and one stop-gained mutation (p.Gln1907*) was detected in the patient II. These mutations may result in a truncated PCNT protein, leading to an inactivated PACT domain corresponding to residue His3138-Trp3216 of PCNT protein. Therefore, the three mutations may cause a deficiency of protein functional activity and result in the phenotypes of primordial dwarfism in the two patients. CONCLUSIONS: Clinical presentations in combination with genetic analyses supported an accurate diagnosis of the two patients with microcephalic osteodysplastic primordial dwarfism type II (MOPD II). In addition, these results have important implications for prenatal genetic screening and genetic counseling for the families.
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Antígenos/genética , Nanismo/genética , Retardo do Crescimento Fetal/genética , Microcefalia/genética , Osteocondrodisplasias/genética , Criança , Pré-Escolar , Nanismo/patologia , Retardo do Crescimento Fetal/patologia , Humanos , Masculino , Microcefalia/patologia , Mutação , Osteocondrodisplasias/patologia , FenótipoRESUMO
Cytochromes P450 (CYPs or P450s) comprise a superfamily of heme-containing monooxygenases that are involved in a variety of biological processes. CYPs have broad utilities in industry, but most exhibit low thermostability, limiting their use on an industrial scale. Highly thermostable enzymes can be obtained from thermophiles in geothermal areas, including hot springs, offshore oil-producing wells and volcanoes. Here, we report the identification of a gene encoding for a thermophilic CYP from the Binh Chau hot spring metagenomic database, which was designated as P450-T2. The deduced amino acid sequence showed the highest identity of 73.15% with CYP203A1 of Rhodopseudomonas palustris, supporting that P450-T2 is a member of the CYP203A subfamily. Recombinant protein expression yielded 541 nm. The optimal temperature and pH of P450-T2 were 50 °C and 8.0, respectively. The half-life of P450-T2 was 50.2 min at 50 °C, and its melting temperature was 56.80 ± 0.08 °C. It was found to accept electrons from all tested redox partners systems, with BmCPR-Fdx2 being the most effective partner. Screening for putative substrates revealed binding of phenolic compounds, such as l-mimosine and emodin, suggesting a potential application of this new thermophilic P450 in the production of the corresponding hydroxylated products.
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Proteínas de Bactérias/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Fontes Termais/microbiologia , Metagenoma , Sequência de Aminoácidos/genética , Proteínas de Bactérias/genética , Proteínas de Bactérias/isolamento & purificação , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/isolamento & purificação , Emodina/metabolismo , Mimosina/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Rodopseudomonas/enzimologia , Rodopseudomonas/genética , Homologia de Sequência de Aminoácidos , Especificidade por Substrato/genética , VietnãRESUMO
Muscular dystrophies are a group of heterogeneous clinical and genetic disorders. Two siblings presented with characteristics like muscular dystrophy, abnormal white matter, and elevated serum creatine kinase level. The high throughput of whole exome sequencing (WES) makes it an efficient tool for obtaining a precise diagnosis without the need for immunohistochemistry. WES was performed in the two siblings and their parents, followed by prioritization of variants and validation by Sanger sequencing. Very rare variants with moderate to high predicted impact in genes associated with neuromuscular disorders were selected. We identified two pathogenic missense variants, c.778C>T (p.H260Y) and c.2987G>A (p.C996Y), in the LAMA2 gene (NM_000426.3), in the homozygous state in two siblings, and in the heterozygous state in their unaffected parents, which were confirmed by Sanger sequencing. Variant c.2987G>A has not been reported previously. These variants may lead to a change in the structure and function of laminin-α2, a member of the family of laminin-211, which is an extracellular matrix protein that functions to stabilize the basement membrane of muscle fibers during contractions. Overall, WES enabled an accurate diagnosis of both patients with LAMA2-related muscular dystrophy and expanded the spectrum of missense variants in LAMA2.
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Background: Ornithine transcarbamylase deficiency (OTCD) is an X- linked recessive disorder and the most common error of the urea cycle, caused by the mutations in the OTC gene. Due to X-inactivation, 15-20% of female carriers present symptoms of OTCD at late onset. Early diagnosis of OTCD by molecular analysis in females is highly desirable. The aim of the study was to identify the mutations in two unrelated Vietnamese girls suspected with OTCD and the carriers in their families for definitive diagnosis and proper counseling. Case Presentation: Two patients presented with an acute encephalopathy at the first admission. Biochemical tests revealed hyperammonemia, hyperlactatemia, elevated glutamine level, elevated transaminase, elevated urinary orotic and uracil acid levels, and disorder of prothrombin time. Brain magnetic resonance imaging indicated cerebral edema. Based on the clinical and laboratory results, the two patients were diagnosed with urea cycle disorders. Therefore, the two patients were managed by stopping feeding, with infused glucose, l-carnitine, l-arginine, and sodium benzoate, and with hemofiltration. The two patients were alert and recovered with normal blood ammonia levels after 72 h of treatment. The family history of patient 1 showed that her brother died at 4 days of age due to a coma and dyspnea, while her parents were asymptomatic. Variable phenotypes were observed in three generations of the patient 2's family, including asymptomatic (mother), affected female adults dying at the first symptom (grandmother and aunt), and affected males dying in the first week of life (uncle, cousin, and siblings). Whole-exome sequencing showed two mutations in the OTC gene, including one novel missense mutation, c.365A>T, in the patient 1 and one previously reported splicing mutation, c.717+1G>A, in the patient 2. The two mutations are evaluated as likely pathogenic and pathogenic, respectively, according to the recommendations of the American College of Medical Genetics and Genomics (ACMG). Genetic analyses in the families indicated the mothers were heterozygous. Conclusion: Clinical, biochemical, and molecular findings accurately diagnosed the two patients with late-onset OTCD. Our results explained the genetic causes and proposed the risk in the patients' families, which could be useful for genetic counseling and monitoring in prenatal diagnosis.
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Warm mix asphalt (WMA) technology, taking advantage of reclaimed asphalt pavements, has gained increasing attention from the scientific community. The determination of technical specifications of such a type of asphalt concrete is crucial for pavement design, in which the asphalt concrete dynamic modulus (E*) of elasticity is amongst the most critical parameters. However, the latter could only be determined by complicated, costly, and time-consuming experiments. This paper presents an alternative cost-effective approach to determine the dynamic elastic modulus (E*) of WMA based on various machine learning-based algorithms, namely the artificial neural network (ANN), support vector machine (SVM), Gaussian process regression (GPR), and ensemble boosted trees (Boosted). For this, a total of 300 samples were fabricated by warm mix asphalt technology. The mixtures were prepared with 0%, 20%, 30%, 40%, and 50% content of reclaimed asphalt pavement (RAP) and modified bitumen binder using Sasobit and Zycotherm additives. The dynamic elastic modulus tests were conducted by varying the temperature from 10 °C to 50 °C at different frequencies from 0.1 Hz to 25 Hz. Various common quantitative indications, such as root mean square error (RMSE), mean absolute error (MAE), and correlation coefficient (R) were used to validate and compare the prediction capability of different models. The results showed that machine learning models could accurately predict the dynamic elastic modulus of WMA using up to 50% RAP and fabricated by warm mix asphalt technology. Out of these models, the Boosted algorithm (R = 0.9956) was found as the best predictor compared with those obtained by ANN-LMN (R = 0.9954), SVM (R = 0.9654), and GPR (R= 0.9865). Thus, it could be concluded that Boosted is a promising cost-effective tool for the prediction of the dynamic elastic modulus (E*) of WMA. This study might help in reducing the cost of laboratory experiments for the determination of the dynamic modulus (E*).
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BACKGROUND: Glycogen storage diseases (GSDs) are clinically and genetically heterogeneous disorders. Overlapping features between liver GSDs are a major challenge in the clinical diagnosis of them. Genetic testing can provide an early and accurate diagnosis of patients suspected with GSDs. CASE PRESENTATION: In this study, we report two siblings born to healthy, non-consanguineous Vietnamese parents with hepatomegaly. The proband presented with hepatomegaly, normal spleen, elevated transaminases, without hypoglycemia, normal lactate dehydrogenase and creatine kinase. Liver biopsy revealed degeneration and swollen hepatocytes, suggesting a diagnosis with GSDs. METHODS: Whole exome sequencing was applied to identify genetic variants in the proband. Variant validation and familial co-segregation analysis were examined using Sanger sequencing. RESULTS: A novel frameshift duplication mutation c.3308_3312dupATGTC (p.L1105Mfs*11) of the PHKA2 gene was identified in the proband and his elder brother at the hemizygous state. This mutation was inherited from their mother. Their father and younger brother were normal genotype. CONCLUSIONS: The two siblings were accurately diagnosed with GSD type XIa. This is the first case report of GSD type IXa in Vietnamese patients with a mutation in the PHKA2 gene. This finding may support for genetics diagnosis of unknown cause of hepatomegaly.
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Doença de Depósito de Glicogênio , Fosforilase Quinase , Idoso , Testes Genéticos , Doença de Depósito de Glicogênio/genética , Humanos , Masculino , Mutação , Fosforilase Quinase/genética , VietnãRESUMO
Cornelia de Lange Syndrome (CdLS) is a rare congenital genetic disease causing abnormal unique facial phenotypes, several defects in organs and body parts, and mental disorder or intellectual disorder traits. Main causes of CdLS have been reported as variants in cohesin complex genes, in which mutations in the NIPBL gene have been estimated to account for up to 80%. Our study included three Vietnamese patients with typical CdLS phenotypes. Whole exome sequencing revealed two known heterozygous mutations c.6697G>A (p.Val2233Met) and c.2602C>T (p.Arg868X), and a novel heterozygous mutation c.4504delG (p.Val1502fsX87) in the NIPBL gene of the three patients. In silico analyses of the identified mutations predicted possible damaging and truncating effects on the NIPBL protein. Inherited analyses in the patients' families showed that all of the mutations are de novo. Our results lead a definitive diagnosis of patients with CdLS and expand the spectrum of mutations in the NIPBL gene. These findings also confirm whole exome sequencing is an efficient tool for genetic screening of CdLS.