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Introduction: X-linked agammaglobulinemia (XLA) is a humoral immunodeficiency disorder characterized by recurrent infections, severe hypogammaglobulinemia, and a deficiency of circulating B cells. While the hallmark clinical manifestations of XLA typically include the respiratory, dermatological, and gastrointestinal systems, renal involvement is infrequent. In this article, we report two cases of XLA with concurrent renal disease, supplemented with a review of documented cases. Case description: The two cases described involve twin brothers, both presenting with respiratory tract infections and renal manifestations. Subsequent genetic testing confirmed the diagnosis of XLA. The younger brother exhibited improvement following intravenous immunoglobulin (IVIG) therapy and anti-infection treatment. Due to financial constraints, the older brother received only anti-infection and symptomatic treatments. Seven months after discharge, the older brother developed nephritis. However, he showed improvement following IVIG treatment. Conclusion: Immune profiling and genetic testing should be considered in male children with recurrent infections to facilitate the effective diagnosis of XLA. Regular monitoring is also imperative to detect and treat immune-mediated renal diseases in patients with XLA.
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Agamaglobulinemia , Doenças Genéticas Ligadas ao Cromossomo X , Imunoglobulinas Intravenosas , Humanos , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/genética , Agamaglobulinemia/complicações , Masculino , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Imunoglobulinas Intravenosas/uso terapêutico , Criança , Pré-EscolarRESUMO
Biofilms produced by Candida albicans present a challenge in treatment with antifungal drug. Enhancing the sensitivity to fluconazole (FLC) is a reasonable method for treating FLC-resistant species. Moreover, several lines of evidence have demonstrated that berberine (BBR) can have antimicrobial effects. The aim of this study was to clarify the underlying mechanism of these effects. We conducted a comparative study of the inhibition of FLC-resistant strain growth by FLC treatment alone, BBR treatment alone, and the synergistic effect of combined FLC and BBR treatment. Twenty-four isolated strains showed distinct biofilm formation capabilities. The antifungal effect of combined FLC and BBR treatment in terms of the growth and biofilm formation of Candida albicans species was determined via checkerboard, time-kill, and fluorescence microscopy assays. The synergistic effect of BBR and FLC downregulated the expression of the efflux pump genes CDR1 and MDR, the hyphal gene HWP1, and the adhesion gene ALS3; however, the gene expression of the transcriptional repressor TUP1 was upregulated following treatment with this drug combination. Furthermore, the addition of BBR led to a marked reduction in cell surface hydrophobicity. To identify resistance-related genes and virulence factors through genome-wide sequencing analysis, we investigated the inhibition of related resistance gene expression by the combination of BBR and FLC, as well as the associated signaling pathways and metabolic pathways. The KEGG metabolic map showed that the metabolic genes in this strain are mainly involved in amino acid and carbon metabolism. The metabolic pathway map showed that several ergosterol (ERG) genes were involved in the synthesis of cell membrane sterols, which may be related to drug resistance. In this study, BBR + FLC combination treatment upregulated the expression of the ERG1, ERG3, ERG4, ERG5, ERG24, and ERG25 genes and downregulated the expression of the ERG6 and ERG9 genes compared with fluconazole treatment alone (p < 0.05).
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Antifúngicos , Berberina , Biofilmes , Candida albicans , Biologia Computacional , Farmacorresistência Fúngica , Fluconazol , Testes de Sensibilidade Microbiana , Berberina/farmacologia , Fluconazol/farmacologia , Candida albicans/efeitos dos fármacos , Candida albicans/genética , Antifúngicos/farmacologia , Farmacorresistência Fúngica/genética , Biologia Computacional/métodos , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Sinergismo Farmacológico , Regulação Fúngica da Expressão Gênica/efeitos dos fármacosRESUMO
Congenital heart disease (CHD) represents a significant risk factor with profound implications for neonatal survival rates and the overall well-being of adult patients. The emergence of induced pluripotent stem cells (iPSCs) and their derived cells, combined with CRISPR technology, high-throughput experimental techniques, and organoid technology, which are better suited to contemporary research demands, offer new possibilities for treating CHD. Prior investigations have indicated that the paracrine effect of exosomes may hold potential solutions for therapeutic intervention. This review provides a summary of the advancements in iPSC-based models and clinical trials associated with CHD while elucidating potential therapeutic mechanisms and delineating clinical constraints pertinent to iPSC-based therapy, thereby offering valuable insights for further deliberation.
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BACKGROUND: Endothelial injury caused by Type 2 diabetes mellitus (T2DM) is considered as a mainstay in the pathophysiology of diabetic vascular complications (DVCs). However, the molecular mechanism of T2DM-induced endothelial injury remains largely unknown. Here, we found that endothelial WW domain-containing E3 ubiquitin protein ligase 2 (WWP2) act as a novel regulator for T2DM-induced vascular endothelial injury through modulating ubiquitination and degradation of DEAD-box helicase 3 X-linked (DDX3X). METHODS: Single-cell transcriptome analysis was used to evaluate WWP2 expression in vascular endothelial cells of T2DM patients and healthy controls. Endothelial-specific Wwp2 knockout mice were used to investigate the effect of WWP2 on T2DM-induced vascular endothelial injury. In vitro loss- and gain-of-function studies were performed to assess the function of WWP2 on cell proliferation and apoptosis of human umbilical vein endothelial cells. The substrate protein of WWP2 was verified using mass spectrometry, coimmunoprecipitation assays and immunofluorescence assays. The mechanism of WWP2 regulation on substrate protein was investigated by pulse-chase assay and ubiquitination assay. RESULTS: The expression of WWP2 was significantly down-regulated in vascular endothelial cells during T2DM. Endothelial-specific Wwp2 knockout in mice significantly aggravated T2DM-induced vascular endothelial injury and vascular remodeling after endothelial injury. Our in vitro experiments showed that WWP2 protected against endothelial injury by promoting cell proliferation and inhibiting apoptosis in ECs. Mechanically, we found that WWP2 is down-regulated in high glucose and palmitic acid (HG/PA)-induced ECs due to c-Jun N-terminal kinase (JNK) activation, and uncovered that WWP2 suppresses HG/PA-induced endothelial injury by catalyzing K63-linked polyubiquitination of DDX3X and targeting it for proteasomal degradation. CONCLUSION: Our studies revealed the key role of endothelial WWP2 and the fundamental importance of the JNK-WWP2-DDX3X regulatory axis in T2DM-induced vascular endothelial injury, suggesting that WWP2 may serve as a new therapeutic target for DVCs.
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Diabetes Mellitus Tipo 2 , Ubiquitina-Proteína Ligases , Humanos , Camundongos , Animais , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/química , Ubiquitina-Proteína Ligases/metabolismo , Regulação para Baixo , Células Endoteliais/metabolismo , Diabetes Mellitus Tipo 2/complicações , Ubiquitinação , Camundongos Knockout , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismoAssuntos
Composição Corporal , Dieta , Humanos , Estudos Prospectivos , Fatores de Risco , Composição Corporal/genéticaRESUMO
Septic shock, a subset of sepsis, is a fatal condition associated with high morbidity and mortality. However, the pathophysiology of septic shock is not fully understood. Moreover, the diagnostic markers employed for identifying septic shock lack optimal sensitivity and specificity. Current treatment protocols for septic shock have not been effective in lowering the mortality rate of patients. Most cells exhibit the capability to release extracellular vesicles (EVs), nanoscale vesicles that play a vital role in intercellular communication. In recent years, researchers have investigated the potential role of EVs in the pathogenesis, diagnosis, and treatment of different diseases, such as oncological, neurological, and cardiovascular diseases, as well as diabetes and septic shock. In this article, we present an overview of the inhibitory and facilitative roles that EVs play in the process of septic shock, the potential role of EVs in the diagnosis of septic shock, and the potential therapeutic applications of both native and engineered EVs in the management of septic shock.
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Doenças Cardiovasculares , Vesículas Extracelulares , Sepse , Choque Séptico , Humanos , Choque Séptico/diagnóstico , Choque Séptico/terapia , Sepse/diagnóstico , Sepse/terapia , Comunicação CelularRESUMO
Exercise is considered as a favorable measure to prevent and treat childhood obesity. However, the underlying mechanisms of exercise-induced beneficial effects and the difference between obese and non-obese individuals are largely unclear. Recently, miR-27a is recognized as a central upstream regulator of proliferator-activated receptor γ (PPAR-γ) in contributing to various physiological and pathological processes. This study aims to explore the possible cause of exercise affecting white adipose tissue (WAT) browning and reversing skeletal muscle insulin resistance in obese/non-obese immature bodies. For simulating the process of childhood obesity, juvenile mice were fed with a basal diet or high-fat diet (HFD) and took 1 or 2 h swimming exercise simultaneously for 10 weeks. The obese animal model was induced by the HFD. We found that exercise hindered HFD-induced body fat development in growing mice. Exercise modified glucolipid metabolism parameters differently in the obese/non-obese groups, and the changes of the 2 h exercise mice were not consistent with the 1 h exercise mice. The level of serum exosomal miR-27a in the non-exercise obese group was increased obviously, which was reduced in the exercise obese groups. Results from bioinformatics analysis and dual-luciferase reporter assay showed that miR-27a targeted PPAR-γ. Exercise stimulated WAT browning; however, the response of obese WAT lagged behind normal WAT. In the HFD-fed mice, 2 h exercise activated the IRS-1/Akt/GLUT-4 signaling pathway in the skeletal muscles. In summary, our findings confirmed that exercise-induced beneficial effects are associated with exercise duration, and the response of obese and non-obese bodies is different. Exosomal miR-27a might be a crucial node for the process of exercise-induced browning of WAT and improving skeletal muscle insulin sensitivity.
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Background: Methylmalonic acidemia (MMA) can display many clinical manifestations, among which acute lymphoblastic leukemia (ALL) has not been reported, and congenital heart disease (CHD) is also rare. Case presentation: We report an MMA case with ALL and CHD in a 5.5-year-old girl. With developmental delay and local brain atrophy in MRI, she was diagnosed with cerebral palsy at 9 months old. Rehabilitation was performed since then. This time she was admitted to hospital because of weakness and widespread bleeding spots. ALL-L2 (pre-B-cell) was confirmed by bone marrow morphology and immunophenotyping. Echocardiography showed patent foramen ovale. The girl was treated with VDLD and CAML chemotherapy, during which she developed seizures, edema and renal insufficiency. Decrease of muscle strength was also found in physical examination. Screening for inherited metabolic disorders showed significantly elevated levels of methylmalonate-2, acetylcarnitine (C2), propionylcarnitine (C3), C3/C2 and homocysteine. Gene analysis revealed a compound heterozygous mutaion in MMACHC (NM_015,560): c.80A > G (p.Gln27Arg) and c.609G > A (p.Trp203*). CblC type MMA was diagnosed. Intramuscular injection of cyanocobalamin and intravenous L-carnitine treatment were applied. The edema vanished gradually, and chemotherapy of small dosage of vindesine was given intermittently when condition permitted. 2 months later, muscle strength of both lower limbs were significantly improved to nearly grade 5. The levels of methylmalonic acid and homocysteine were improved. Conclusion: Metabolic disease screening and gene analysis are very necessary for diseases with complex clinical symptoms. ALL can be a rare manifestation for MMA. Synopsis: We report a case of methylmalonic acidemia with acute lymphoblastic leukemia and congenital heart disease, which uncovered the importance of genetic testing and metabolic diseases screening in patients with multiple systemic organ involvement.
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OBJECTIVE: Peripheral helper T (Tph) cells interact with B cells and promote immune responses at sites of ectopic lymphoid structures (ELSs). To assess the characteristics of Tph cells, we investigated the phenotype of T helper (Th) cells in patients with SLE and the underlying competitive binding mechanisms using cytokine-mediated signal transducer and activator of transcription (STAT) factors. METHODS: Peripheral blood mononuclear cells from SLE patients and healthy controls were analysed for phenotypic identification. Serum cytokine levels were detected using Luminex assays. In vitro culture was performed to assess cytokine-induced conversion of phenotypes and transcriptional regulation using flow cytometry and PCR. Chromatin immunoprecipitation was used to evaluate STAT binding and histone modifications. RESULTS: CXCR5-PD-1+Tph-like cells were increased in SLE patients and showed strong association with disease activity and renal involvement. Serum IFN-α levels were increased and associated with Tph frequency. IFN-α promoted the differentiation of IL-10-producing CXCR5-PD-1+Tph-like cells, increased the responsiveness of IL-2 and induced the conversion of Tfh-like cells to Tph-like cells. STAT5 gained a competitive advantage and bound to the BCL6 locus at the expense of STAT1, accompanied by suppression of H3K4me3. Finally, anti-IFNAR1 decreased the differentiation of Tph-like cells, thereby suppressing the generation of CD38highCD27highplasmablasts. CONCLUSION: Tph cells might be crucial makers to effectively reflect disease activity level in SLE patients. The finding that synergy of IFN-α and IL-2 increases Tph cells through competitive transcriptional regulation could be one of the mechanisms responsible for pathological formation of ELSs and helpful for selection of individualized therapeutic approaches for SLE.
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Lúpus Eritematoso Sistêmico , Células T Auxiliares Foliculares , Humanos , Receptor de Morte Celular Programada 1/metabolismo , Leucócitos Mononucleares/metabolismo , Ligação Competitiva , Interleucina-2 , Interleucinas/metabolismo , Linfócitos T Auxiliares-Indutores , Receptores CXCR5/metabolismo , Citocinas/metabolismo , Lúpus Eritematoso Sistêmico/metabolismoRESUMO
Congenital heart disease (CHD) is the most common noninfectious cause of death during the neonatal stage. T-box transcription factor 1 (TBX1) is the main genetic determinant of 22q11.2 deletion syndrome (22q11.2DS), which is a common cause of CHD. Moreover, ferroptosis is a newly discovered kind of programmed cell death. In this study, the interaction among TBX1, miR-193a-3p, and TGF-ß2 was tested using quantitative reverse transcription polymerase chain reaction (qRT-PCR), Western blotting, and dual-luciferase reporter assays. TBX1 silencing was found to promote TGF-ß2 messenger ribonucleic acid (mRNA) and protein expression by downregulating the miR-193a-3p levels in H9c2 cells. In addition, the TBX1/miR-193a-3p/TGF-ß2 axis was found to promote ferroptosis based on assessments of lipid reactive oxygen species (ROS) levels, Fe2+ concentrations, mitochondrial ROS levels, and malondialdehyde (MDA) contents; Cell Counting Kit-8 (CCK-8) assays and transmission electron microscopy; and Western blotting analysis of glutathione peroxidase 4 (GPX4), nuclear factor erythroid 2-related factor 2 (NRF2), heme oxygenase-1 (HO-1), NADPH oxidase 4 (NOX4), and acyl-CoA synthase long-chain family member 4 (ACSL4) protein expression. The protein expression of NRF2, GPX4, HO-1, NOX4, and ACSL4 and the level of MDA in human CHD specimens were also detected. In addition, TBX1 and miR-193a-3p expression was significantly downregulated and TGF-ß2 levels were high in human embryonic CHD tissues, as indicated by the H9c2 cell experiments. In summary, the TBX1/miR-193a-3p/TGF-ß2 axis mediates CHD by inducing ferroptosis in cardiomyocytes. TGF-ß2 may be a target gene for CHD diagnosis and treatment in children.
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Ferroptose/genética , Cardiopatias Congênitas/genética , Proteínas com Domínio T/metabolismo , Fator de Crescimento Transformador beta2/metabolismo , Células HEK293 , Humanos , TransfecçãoRESUMO
BACKGROUND: Chronic kidney disease (CKD) is characterized by high morbidity and mortality and is difficult to cure. Renal interstitial fibrosis (RIF) is a major determinant of, and commonly occurs within, CKD progression. Epithelial mesenchymal transition (EMT) has been identified as a crucial process in triggering renal interstitial fibrosis (RIF). Interleukin-like EMT inducer (ILEI) is an important promotor of EMT; this study aims to elucidate the mechanisms involved. METHODS: Male C57BL6/J mouse were randomly divided into 6 groups: sham (n = 10), sham with negative control (NC) shRNA (sham + NC, n = 10), sham with ILEI shRNA (sham + shILEI, n = 10), unilateral ureteral obstruction (UUO, n = 10), UUO with NC (UUO + NC, n = 10) and UUO with ILEI shRNA (UUO + shILEI, n = 10). Hematoxylin and eosin (H&E), Masson, and immunohistochemical (IHC) staining and western blotting (WB) were performed on murine kidney tissue to identify the function and mechanism of ILEI in RIF. In vitro, ILEI was overexpressed to induce EMT in HK2 cells and analyzed via transwell, WB, real-time PCR, and co-immunoprecipitation. Finally, tissue from 12 pediatric CKD patients (seven with RIF and five without RIF) were studied with H&E, Masson, and IHC staining. RESULTS: Our in vitro model revealed that ILEI facilitates RIF in the UUO model via the Akt and ERK pathways. Further experiments in vivo and in vitro revealed that ILEI promotes renal tubular EMT by binding and activating leukemia inhibitory factor receptor (LIFR), in which phosphorylation of Akt and ERK is involved. We further find markedly increased expression levels of ILEI and LIFR in kidneys from pediatric CKD patients with RIF. CONCLUSION: Our results indicate that ILEI may be a useful biomarker for renal fibrosis and a potential therapeutic target for modulating RIF.
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Nefropatias , Insuficiência Renal Crônica , Animais , Criança , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal , Fibrose , Humanos , Nefropatias/metabolismo , Subunidade alfa de Receptor de Fator Inibidor de Leucemia/metabolismo , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de OSM-LIF/metabolismo , Fator de Crescimento Transformador beta1/metabolismoRESUMO
OBJECTIVES: This study aimed to evaluate the level of medical students' self-directed learning (SDL) ability in mainland China and to identify its modifiable influencing factors for medical educators to take measures to improve medical professionals' ability in SDL. DESIGN: This was a cross-sectional study conducted between January and June 2019. SETTING: This study involved students from five medical colleges located in the cities of Shenyang, Binzhou, Xuzhou, Shanghai and Guangzhou of mainland China. PARTICIPANTS: Participants included 365 medical students and residents sampled by the stratified clustered random method from five medical colleges. METHODS: The t-test, F-test and multiple linear regression analyses were performed to test the association between personal and contextual factors of medical students and SDL. RESULTS: The mean total SDL score was 76.12 (SD=10.96), implying that Chinese mainland medical students had moderate SDL ability. A univariate analysis found that the personal characteristics of confidence, students' enjoyment of their specialty, utilisation of library resources, learning goals and habits and academic performance as well as the contextual factors of age, gender, learning resources, family income and group discussion were significantly associated with the total SDL score (p<0.05). Multiple linear regression analyses showed that academic performance, learning goals, confidence, learning resources, utilisation of library resources, family income and age were significantly associated with the total SDL score (p<0.05). CONCLUSION: Our study indicated that the contextual factors of learning resources, family income and age as well as the personal factors of academic performance, learning goals, confidence and utilisation of library resources were associated with medical students' SDL ability in mainland China. It may be advisable to implement appropriate teaching strategies to improve students' confidence and assist them establish learning goals, as well as to amplify school learning resources and encourage students to use them fully.
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Estudantes de Medicina , China , Estudos Transversais , Currículo , Humanos , AprendizagemRESUMO
Short ribpolydactyly syndrome type III (SRPS3) is a lethal perinatal skeletal disorder consisting of polydactyly and multisystem organ abnormalities. To further assess the pathogenicity of two pairs of compound heterozygotes and to search for novel molecular etiology, Xrays and hematoxylin and eosin staining were conducted in three cases: Two retrospective samples and a newly identified patient with SRPS3. In addition, nextgeneration sequencing was used to evaluate a fetus with SRPS3. Typical radiological features of the three cases included a long, narrow thorax with short ribs, shortened long bones, spurs at the metaphysis of the long bones and congenital bowing of the femurs. The present study also observed atypical histopathological changes, together with the absence of proliferation and abundance of retaining cartilage in the primary spongiosum. In addition, two novel compound heterozygous variants were identified in the dynein cytoplasmic 2 heavy chain 1 (DYNC2H1) gene of the fetus: NM_001080463.1, c.6591_6593delTGG (chr11:103055738103055740); NM_001080463.1, c.7883T>C (chr11:103070000). The findings of the present study provided further confirmation of the pathogenicity of two compound heterozygous variants in two retrospective samples and identified novel compound heterozygous variants. These findings may improve our knowledge of the histopathological and radiological changes in patients with SRPS3 and the relative effects of DYNC2H1 variants. The findings of the present study may facilitate the clinical and molecular diagnosis of SRPS3.
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Dineínas do Citoplasma/metabolismo , Radiografia/métodos , Síndrome de Costela Curta e Polidactilia/diagnóstico por imagem , Adulto , Dineínas do Citoplasma/genética , Feminino , Feto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Linhagem , Estudos Retrospectivos , Síndrome de Costela Curta e Polidactilia/genética , Síndrome de Costela Curta e Polidactilia/patologiaRESUMO
Mica is a naturally abundant layered silicate mineral that has higher strength than other layered silicate minerals, but its inherent brittleness limits its application in some fields. In this work, mica was ultrasonically exfoliated into a single-layered nanomaterial after thermal activation, acidification, sodium replacement, and cetyltrimethylammonium bromide (CTAB) intercalation and then modified with ureido-pyrimidinone (UPy)-based PEG chains. Vacuum-assisted self-assembly was used to construct supramolecularly modified single-layered mica into bulk materials, in which the mica nanosheets were stacked into mica paper. The reversible quadruple hydrogen-bonded UPy moieties provided a high binding constant and significantly improved the strength and toughness of the obtained mica paper. These force-induced assembled mica papers showed significantly improved tensile strength and toughness compared with pure mica paper and simultaneously maintained the heat resistance of the mica materials, which may be good candidates for the substrates of flexible sensors working at higher temperatures.
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Hydroxyapatite (HA) is the main inorganic component of human bones and teeth. It has good biocompatibility and bioactivity, which promotes its good application prospects in the field of bone drug carriers. In this study, tetraethylenepentamine-graphene (rGO-TEPA)/CaCO3:HA composite microspheres were prepared via microwave hydrothermal synthesis using rGO-TEPA/CaCO3 solid microspheres as intermediates. Furthermore, the incompletely transformed CaCO3 was removed by soaking in a citric acid buffer to obtain rGO-TEPA/HA hollow composite microspheres. The two types of as-prepared composite microspheres exhibited sea urchin-like structures, large BET surface areas, and good dispersibility. Mouse preosteoblast cells (MC3T3-E1) were used for in vitro cytotoxicity experiments. The in vitro cell viability test showed that the two composite drug carriers exhibited noncytotoxicity. Moreover, the doxorubicin (DOX) loading and releasing investigations revealed that the two types of prepared carriers had mild storage-release behaviors and good pH responsiveness. Hence, these rGO-TEPA/HA hollow microspheres have promising applications as bone drug carriers.
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Materiais Biomiméticos , Osso e Ossos/metabolismo , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Durapatita , Grafite , Microesferas , Ouriços-do-Mar , Animais , Osso e Ossos/citologia , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/farmacologia , Etilenodiaminas , Concentração de Íons de Hidrogênio , Camundongos , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Células-Tronco/efeitos dos fármacosRESUMO
Congenital disorders of glycosylation (CDG) are a group of genetic, mostly multisystem disorders, which often involve the central nervous system. ALG3-CDG is one the some 130 known CDG. Here we report two siblings with a severe phenotype and intrauterine death. Whole-exome sequencing revealed two novel variants in ALG3: NM_005787.6:c.512G>T (p.Arg171Leu) inherited from the mother and NM_005787.6:c.511C>T (p.Arg171Trp) inherited from the father.
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Sistema Nervoso Central/metabolismo , Defeitos Congênitos da Glicosilação/genética , Genes Letais/genética , Manosiltransferases/genética , Feto Abortado/patologia , Sistema Nervoso Central/patologia , Defeitos Congênitos da Glicosilação/metabolismo , Defeitos Congênitos da Glicosilação/patologia , Feminino , Humanos , Masculino , Mães , Mutação/genética , Fenótipo , Irmãos , Sequenciamento do ExomaRESUMO
BACKGROUND: DNA methylation is a molecular modification of DNA that is vital and occurs in gene expression. In cancer tissues, the 5'-C-phosphate-G-3'(CpG) rich regions are abnormally hypermethylated or hypomethylated. Therefore, it is useful to find out the diseased CpG sites by employing specific methods. CpG sites are highly correlated with each other within the same gene or the same CpG island. OBJECTIVE: Based on this group effect, we proposed an efficient and accurate method for selecting pathogenic CpG sites. METHODS: Our method aimed to combine a L1/2 regularized solver and a central node fully connected network to penalize group constrained logistic regression model. Consequently, both sparsity and group effect were brought in with respect to the correlated regression coefficients. RESULTS: Extensive simulation studies were used to compare our proposed approach with existing mainstream regularization in respect of classification accuracy and stability. The simulation results show that a greater predictive accuracy was attained in comparison to previous methods. Furthermore, our method was applied to over 20000 CpG sites and verified using the ovarian cancer data generated from Illumina Infinium HumanMethylation 27K Beadchip. In the result of the real dataset, not only the indicators of predictive accuracy are higher than the previous methods, but also more CpG sites containing genes are confirmed pathogenic. Additionally, the total number of CpG sites chosen is less than other methods and the results show higher accuracy rates in comparison to other methods in simulation and DNA methylation data. CONCLUSION: The proposed method offers an advanced tool to researchers in DNA methylation and can be a powerful tool for recognizing pathogenic CpG sites.
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Ilhas de CpG/fisiologia , Metilação de DNA/fisiologia , Modelos Logísticos , Neoplasias Ovarianas/patologia , Algoritmos , Simulação por Computador , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Sensibilidade e EspecificidadeRESUMO
The pathogeneses of recurrent fever are quite complicated when excluding repeated infections. Recurrent fever is a common symptom for autoinflammatory diseases, relapse of Systemic-onset juvenile idiopathic arthritis (SoJIA) and recurrent Kawasaki disease (KD). There are no specific diagnostic laboratory tests for the diseases. Some studies showed that KD was the precursor of hemophagocytic lymphohistiocytosis (HLH). Macrophage activation syndrome (MAS) is another form of HLH in SoJIA. Cytokine disturbances are considered to be involved in the pathogenesis of the diseases. We describe a Chinese female toddler that developed three separate fever episodes with eventual diagnose of SoJIA within about 10 months. The first episode was diagnosed as IKD, immunoglobulin nonresponsive KD, and HLH. The second and third episodes were diagnosed as IKD and SoJIA, respectively. The fever was hard to be relieved by antipyretics, and the peak axillary temperature was above 40°C. For every fever episode, infections were excluded. For the first episode, trends over time of hemoglobin, platelets, fibrinogen, and triglycerides indicated HLH, which was finally diagnosed and treated according to the HLH-2004 protocol. For the second episode 6 months later, after excluding an HLH relapse and infections, IKD was finally diagnosed. Oral aspirin was administered, and the HLH treatment was ceased. The third episode occurred 3 months later, and SoJIA was finally diagnosed. For each episode, except for relative tests, we only tested for cytokines interleukin-1ß, interleukin-6, and interferon-γ, due to limited laboratory test availability. These cytokines were elevated during remission and rose much higher in the fever phases. The case showed the difficulty to differentiating the recurrent fever in clinical practice. Surveillance of routine laboratory parameters over time might reveal a trend that indicates possible disease, even when parameter values do not meet diagnostic criteria. Changes in cytokine profiles are promising markers for differentiating recurrent fever diseases in future. An unknown immunological defect for the case may contribute to the recurrent immunological insults, and we are following up the recurrence of fever episode.