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1.
Int J Mol Sci ; 22(21)2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34769416

RESUMO

Rabies is a deadly viral disease caused by the rabies virus (RABV), transmitted through a bite of an infected host, resulting in irreversible neurological symptoms and a 100% fatality rate in humans. Despite many aspects describing rabies neuropathogenesis, numerous hypotheses remain unanswered and concealed. Observations obtained from infected primary neurons or mouse brain samples are more relevant to human clinical rabies than permissive cell lines; however, limitations regarding the ethical issue and sample accessibility become a hurdle for discovering new insights into virus-host interplays. To better understand RABV pathogenesis in humans, we generated human-induced pluripotent stem cell (hiPSC)-derived neurons to offer the opportunity for an inimitable study of RABV infection at a molecular level in a pathologically relevant cell type. This study describes the characteristics and detailed proteomic changes of hiPSC-derived neurons in response to RABV infection using LC-MS/MS quantitative analysis. Gene ontology (GO) enrichment of differentially expressed proteins (DEPs) reveals temporal changes of proteins related to metabolic process, immune response, neurotransmitter transport/synaptic vesicle cycle, cytoskeleton organization, and cell stress response, demonstrating fundamental underlying mechanisms of neuropathogenesis in a time-course dependence. Lastly, we highlighted plausible functions of heat shock cognate protein 70 (HSC70 or HSPA8) that might play a pivotal role in regulating RABV replication and pathogenesis. Our findings acquired from this hiPSC-derived neuron platform help to define novel cellular mechanisms during RABV infection, which could be applicable to further studies to widen views of RABV-host interaction.

2.
Biomed Rep ; 15(4): 82, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34512970

RESUMO

Non-invasive prenatal diagnosis (NIPD) of isolated cell-free DNA from maternal plasma has been applied to detect monogenic diseases in the fetus. Droplet digital PCR (ddPCR) is a sensitive and quantitative technique for NIPD. In the present study, the development and evaluation of ddPCR-based assays for common α and ß-thalassemia variants amongst the Asian population was described; specifically, Southeast Asian (SEA) deletion, HbE, and 41/42 (-CTTT). SEA is caused by deletion of a 20 kb region surrounding the α-globin gene, whilst HbE and 41/42 (-CTTT) are caused by point mutations on the ß-globin gene. Cell-free DNA samples from 46 singleton pregnant women who were carriers of these mutations were isolated and quantified using ddPCR with specially designed probes for each target allele. Allelic copy number calculation and likelihood ratio tests were used to classify fetal genotypes. Classification performances were evaluated against ground truth fetal genotypes obtained from conventional amniocentesis. Copy number variation analysis of SEA deletion accurately classified fetal genotypes in 20 out of 22 cases with an area under the receiver operating characteristic curve of 0.98 for detecting Hb Bart's hydrops fetalis. For HbE cases, 10 out of 16 samples were correctly classified, and three were inconclusive. For 41/42 (-CTTT) cases, 2 out of 8 were correctly classified, and four were inconclusive. The correct genotype was not rejected in any inconclusive case and may be resolved with additional ddPCR experiments. These results indicate that ddPCR-based analysis of maternal plasma can become an accurate and effective NIPD for SEA deletion α-(0) thalassemia. Although the performance of ddPCR on HbE and 41/42 (-CTTT) mutations were not sufficient for clinical application, these results may serve as a foundation for future works in this field.

3.
Cancer Gene Ther ; 2021 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-34548635

RESUMO

Cholangiocarcinoma (CCA), a lethal malignancy of the biliary epithelium, is the second most common primary liver cancer. The poor prognosis of CCA is due to the high rate of tumour invasion and distant metastasis. We found that the RNA-binding protein LIN28B, a known regulator of microRNA biogenesis, stem cell maintenance, and oncogenesis, is expressed in a subpopulation of CCA patients. To further investigate the potential role of LIN28B in CCA pathogenesis, we studied the effect of LIN28B overexpression in the cholangiocyte cell line MMNK-1 and cholangiocarcinoma cell lines HuCCT-1 and KKU-214. Here, we show that enhanced LIN28B expression promoted cancer stem cell-like properties in CCA, including enhanced cell migration, epithelial-to-mesenchymal transition (EMT), increased cell proliferation and spheroid formation. Proteomic analysis revealed TGF-ß-induced protein (TGFBI) as a novel LIN28B target gene, and further analysis showed upregulation of other components of the TGF-ß signalling pathway, including TGF-ß receptor type I (TGFBRI) expression and cytokine TGFB-I, II and III secretion. Importantly, the small molecule TGF-ß inhibitor SB431542 negated the effects of LIN28B on both cell migration and clonogenic potential. Overexpression of TGFBI alone promoted cholangiocarcinoma cell migration and EMT changes, but not spheroid formation, suggesting that TGFBI partially contributes to LIN28B-mediated aggressive cell behaviour. These observations are consistent with a model in which TGF-ß and LIN28B work together to form a positive feedback loop during cholangiocarcinoma metastasis and provide a therapeutic intervention opportunity.

4.
Nat Med ; 27(10): 1735-1743, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34526699

RESUMO

Federated learning (FL) is a method used for training artificial intelligence models with data from multiple sources while maintaining data anonymity, thus removing many barriers to data sharing. Here we used data from 20 institutes across the globe to train a FL model, called EXAM (electronic medical record (EMR) chest X-ray AI model), that predicts the future oxygen requirements of symptomatic patients with COVID-19 using inputs of vital signs, laboratory data and chest X-rays. EXAM achieved an average area under the curve (AUC) >0.92 for predicting outcomes at 24 and 72 h from the time of initial presentation to the emergency room, and it provided 16% improvement in average AUC measured across all participating sites and an average increase in generalizability of 38% when compared with models trained at a single site using that site's data. For prediction of mechanical ventilation treatment or death at 24 h at the largest independent test site, EXAM achieved a sensitivity of 0.950 and specificity of 0.882. In this study, FL facilitated rapid data science collaboration without data exchange and generated a model that generalized across heterogeneous, unharmonized datasets for prediction of clinical outcomes in patients with COVID-19, setting the stage for the broader use of FL in healthcare.


Assuntos
COVID-19/fisiopatologia , Aprendizado de Máquina , Avaliação de Resultados em Cuidados de Saúde , COVID-19/terapia , COVID-19/virologia , Registros Eletrônicos de Saúde , Humanos , Prognóstico , SARS-CoV-2/isolamento & purificação
5.
EMBO J ; 40(18): e108345, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34337769

RESUMO

PIWI-interacting RNAs (piRNAs) are germline-specific small RNAs that form effector complexes with PIWI proteins (Piwi-piRNA complexes) and play critical roles for preserving genomic integrity by repressing transposable elements (TEs). Drosophila Piwi transcriptionally silences specific targets through heterochromatin formation and increases histone H3K9 methylation (H3K9me3) and histone H1 deposition at these loci, with nuclear RNA export factor variant Nxf2 serving as a co-factor. Using ChEP and DamID-seq, we now uncover a Piwi/Nxf2-dependent target association with nuclear lamins. Hi-C analysis of Piwi or Nxf2-depleted cells reveals decreased intra-TAD and increased inter-TAD interactions in regions harboring Piwi-piRNA target TEs. Using a forced tethering system, we analyze the functional effects of Piwi-piRNA/Nxf2-mediated recruitment of piRNA target regions to the nuclear periphery. Removal of active histone marks is followed by transcriptional silencing, chromatin conformational changes, and H3K9me3 and H1 association. Our data show that the Piwi-piRNA pathway can induce stepwise changes in nuclear architecture and chromatin state at target loci for transcriptional silencing.

6.
Bioinformatics ; 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34196671

RESUMO

MOTIVATION: MHC-peptide binding prediction has been widely used for understanding the immune response of individuals or populations, each carrying different MHC molecules as well as for the development of immunotherapeutics. The results from MHC-peptide binding prediction tools are mostly reported as a predicted binding affinity (IC50) and the percentile rank score, and global thresholds e.g. IC50 value < 500 nM or percentile rank < 2% are generally recommended for distinguishing binding peptides from non-binding peptides. However, it is difficult to evaluate statistically the probability of an individual peptide binding prediction to be true or false solely considering predicted scores. Therefore, statistics describing the overall global false discovery rate (FDR) and local FDR, also called posterior error probability (PEP) are required to give statistical context to the natively produced scores. RESULT: We have developed an algorithm and code implementation, called MHCVision, for estimation of FDR and PEP values for the predicted results of MHC-binding prediction from the NetMHCpan tool. MHCVision performs parameter estimation using a modified expectation maximisation (EM) framework for a two-component beta mixture model, representing the distribution of true and false scores of the predicted data set. We can then estimate the PEP of an individual peptide's predicted score, and conversely the probability that it is true. We demonstrate that the use of global FDR and PEP estimation can provide a better trade-off between sensitivity and precision over using currently recommended thresholds from tools. AVAILABILITY: https://github.com/PGB-LIV/MHCVision. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

7.
J Radiat Res ; 62(3): 483-493, 2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-33899102

RESUMO

We developed a confidence interval-(CI) assessing model in multivariable normal tissue complication probability (NTCP) modeling for predicting radiation-induced liver disease (RILD) in primary liver cancer patients using clinical and dosimetric data. Both the mean NTCP and difference in the mean NTCP (ΔNTCP) between two treatment plans of different radiotherapy modalities were further evaluated and their CIs were assessed. Clinical data were retrospectively reviewed in 322 patients with hepatocellular carcinoma (n = 215) and intrahepatic cholangiocarcinoma (n = 107) treated with photon therapy. Dose-volume histograms of normal liver were reduced to mean liver dose (MLD) based on the fraction size-adjusted equivalent uniform dose. The most predictive variables were used to build the model based on multivariable logistic regression analysis with bootstrapping. Internal validation was performed using the cross-validation leave-one-out method. Both the mean NTCP and the mean ΔNTCP with 95% CIs were calculated from computationally generated multivariate random sets of NTCP model parameters using variance-covariance matrix information. RILD occurred in 108/322 patients (33.5%). The NTCP model with three clinical and one dosimetric parameter (tumor type, Child-Pugh class, hepatitis infection status and MLD) was most predictive, with an area under the receiver operative characteristics curve (AUC) of 0.79 (95% CI 0.74-0.84). In eight clinical subgroups based on the three clinical parameters, both the mean NTCP and the mean ΔNTCP with 95% CIs were able to be estimated computationally. The multivariable NTCP model with the assessment of 95% CIs has potential to improve the reliability of the NTCP model-based approach to select the appropriate radiotherapy modality for each patient.


Assuntos
Hepatopatias/etiologia , Neoplasias Hepáticas/complicações , Modelos Biológicos , Probabilidade , Lesões por Radiação/complicações , Intervalos de Confiança , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada
8.
Mol Cell Proteomics ; 18(12): 2478-2491, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31591261

RESUMO

Typical analyses of mass spectrometry data only identify amino acid sequences that exist in reference databases. This restricts the possibility of discovering new peptides such as those that contain uncharacterized mutations or originate from unexpected processing of RNAs and proteins. De novo peptide sequencing approaches address this limitation but often suffer from low accuracy and require extensive validation by experts. Here, we develop SMSNet, a deep learning-based de novo peptide sequencing framework that achieves >95% amino acid accuracy while retaining good identification coverage. Applications of SMSNet on landmark proteomics and peptidomics studies reveal over 10,000 previously uncharacterized HLA antigens and phosphopeptides, and in conjunction with database-search methods, expand the coverage of peptide identification by almost 30%. The power to accurately identify new peptides of SMSNet would make it an invaluable tool for any future proteomics and peptidomics studies, including tumor neoantigen discovery, antibody sequencing, and proteome characterization of non-model organisms.


Assuntos
Aprendizado Profundo , Peptídeos/análise , Análise de Sequência de Proteína/métodos , Sequência de Aminoácidos , Conjuntos de Dados como Assunto , Antígenos HLA/análise , Humanos , Fosfopeptídeos/análise , Espectrometria de Massas em Tandem
9.
Commun Biol ; 2: 263, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31341962

RESUMO

Genome hybridization is an important evolutionary event that gives rise to species with novel capabilities. However, the merging of distinct genomes also brings together incompatible regulatory networks that must be resolved during the course of evolution. Understanding of the early stages of post-hybridization evolution is particularly important because changes in these stages have long-term evolutionary consequences. Here, via comparative transcriptomic analyses of two closely related, recently hybridized Trichosporon fungi, T. coremiiforme and T. ovoides, and three extant relatives, we show that early post-hybridization evolutionary processes occur separately at the gene sequence and gene expression levels but together contribute to the stabilization of hybrid genome and transcriptome. Our findings also highlight lineage-specific consequences of genome hybridization, revealing that the transcriptional regulatory dynamics in these hybrids responded completely differently to gene loss events: one involving both subgenomes and another that is strictly subgenome-specific.


Assuntos
Genoma Fúngico , Hibridização Genética , Transcriptoma , Trichosporon/genética , Regulação Fúngica da Expressão Gênica
10.
Mol Neurobiol ; 56(11): 7822-7835, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31124079

RESUMO

Major depressive disorder (MDD) is characterized by signaling aberrations in interleukin (IL)-6, IL-10, beta-endorphins as well as µ (MOR) and κ (KOR) opioid receptors. Here we examined whether these biomarkers may aid in the classification of unknown subjects into the target class MDD. The aforementioned biomarkers were assayed in 60 first-episode, drug-naïve depressed patients and 30 controls. We used joint principal component analysis (PCA) performed on all subjects to check whether subjects cluster by classes; support vector machine (SVM) with 10-fold validation; and linear discriminant analysis (LDA) and SIMCA performed on calibration and validation sets and we computed the figures of merit and learnt from the data. PCA shows that both groups were well separated using the first three PCs, while correlation loadings show that all five biomarkers have discriminatory value. SVM and LDA yielded an accuracy of 100% in validation samples. Using SIMCA, there was a highly significant discrimination of both groups (model-to-model distance = 110.2); all biomarkers showed a significant discrimination and modeling power, while 100% of the patients were authenticated as MDD cases with a specificity of 93.3%. We have delineated that MDD is a distinct class with respect to neuro-immune and opioid biomarkers and that future unknown subjects can be authenticated as having MDD using this SIMCA fingerprint. Precision psychiatry should employ SIMCA to (a) authenticate patients as belonging to the claimed target class and identify other subjects as outsiders, members of another class, or aliens; and (b) acquire knowledge through learning from the data by constructing a biomarker fingerprint of the target class.


Assuntos
Analgésicos Opioides/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/imunologia , Adolescente , Adulto , Idoso , Biomarcadores/metabolismo , Análise Discriminante , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise de Componente Principal , Reprodutibilidade dos Testes , Máquina de Vetores de Suporte , Adulto Jovem
11.
BMC Bioinformatics ; 20(1): 270, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138107

RESUMO

BACKGROUND: Immunotherapy is an emerging approach in cancer treatment that activates the host immune system to destroy cancer cells expressing unique peptide signatures (neoepitopes). Administrations of cancer-specific neoepitopes in the form of synthetic peptide vaccine have been proven effective in both mouse models and human patients. Because only a tiny fraction of cancer-specific neoepitopes actually elicits immune response, selection of potent, immunogenic neoepitopes remains a challenging step in cancer vaccine development. A basic approach for immunogenicity prediction is based on the premise that effective neoepitope should bind with the Major Histocompatibility Complex (MHC) with high affinity. RESULTS: In this study, we developed MHCSeqNet, an open-source deep learning model, which not only outperforms state-of-the-art predictors on both MHC binding affinity and MHC ligand peptidome datasets but also exhibits promising generalization to unseen MHC class I alleles. MHCSeqNet employed neural network architectures developed for natural language processing to model amino acid sequence representations of MHC allele and epitope peptide as sentences with amino acids as individual words. This consideration allows MHCSeqNet to accept new MHC alleles as well as peptides of any length. CONCLUSIONS: The improved performance and the flexibility offered by MHCSeqNet should make it a valuable tool for screening effective neoepitopes in cancer vaccine development.


Assuntos
Antígenos de Histocompatibilidade Classe I/metabolismo , Modelos Biológicos , Redes Neurais de Computação , Software , Alelos , Animais , Área Sob a Curva , Bases de Dados de Proteínas , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Camundongos , Peptídeos/química , Peptídeos/metabolismo , Ligação Proteica , Proteoma/metabolismo
12.
Fungal Genet Biol ; 130: 31-42, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31026590

RESUMO

Delineation and characterization of genera in Trichosporonales (Agaricomycotina, Basidiomycota) was performed using 24 haploid and 3 naturally occurring hybrid genomes, with 3 Tremellales genomes used as outgroups. Orthologous group analysis of those genomes showed presence-absence patterns of orthologs that were consistent with the genus classifications. Many shared unique orthologs were identified in the well-supported lineages (genera Apiotrichum and Trichosporon), supporting the definitions of the genera Apiotrichum and Trichosporon from a genomic perspective. Specifically, we obtained 24 and 285 genus-specific genes from eight Apiotrichum and five Trichosporon species, respectively, and propose that these genus-specific genes can be used for delineation of those genera. On the other hand, the genus Cutaneotrichosporon shared only one genus-specific gene among eight genomes, indicating that this genus definition might require re-examination based on genomic data. In addition, taxonomic revisions are presented in this study, including the proposal of two genera, Pascua and Prillingera. Because genomic data can be systematically obtained and analyzed to compare species from a comprehensive viewpoint, they can be used not only to reconstruct reliable phylogenetic trees, but also to re-examine the definitions of taxonomic classifications. To our knowledge, this is the first report to discuss the 'natural system' of genus level classification in fungi based on genomic data.


Assuntos
Basidiomycota/classificação , Basidiomycota/genética , Genoma Fúngico , Genômica , Filogenia , Basidiomycota/isolamento & purificação , Proteínas Fúngicas/genética , Genes Fúngicos , Haploidia , Fenótipo , Análise de Sequência , Trichosporon/classificação , Trichosporon/genética , Ubiquinona
13.
Metab Brain Dis ; 34(1): 267-282, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30467771

RESUMO

Stable phase schizophrenia is characterized by altered patterning in tryptophan catabolites (TRYCATs) and memory impairments, which are associated with PHEMN (psychosis, hostility, excitation, mannerism and negative) and DAPS (depression, anxiety and physio-somatic) symptoms. This study was carried out to examine the association between TRYCAT patterning, memory impairments, psychopathological features and health-related quality of life (HR-QoL) in schizophrenia. The World Health Organization (WHO) QoL instrument-Abbreviated version (WHO-QoL-BREF), IgA/IgM responses to TRYCATs, cognitive tests, Scale for the Assessment of Negative Symptoms (SANS), Hamilton and Depression (HAMD) and Anxiety (HAMA) Rating Scales and the Fibromyalgia and Chronic Fatigue Syndrome Rating Scale (FF) were measured in 80 schizophrenia patients and 40 controls. Neural Network analysis shows that the total HR-Qol score is best predicted by (in descending order) HAMA, FF, HAMD, and psychosis. Partial least Squares (PLS) analysis shows that 56.7% of the variance in the WHO-QoL scores is explained by PHEMN / DAPS symptoms, while 64.3% of the variance in those symptoms is explained by TRYCAT patterning and episodic/semantic memory impairments. IgA responses to picolinic acid, xanthurenic acid and 3-hydroxy-kynurenine (all negatively) and anthranilic acid (positively) have highly significant indirect effects on WHO-QoL scores, which are completely mediated by cognitive impairments and PHEMN / DAPS symptoms. The results show that lowered HR-Qol in schizophrenia is strongly associated with noxious TRYCATs and that these effects are mediated by impairments in episodic / semantic memory and schizophrenia phenomenology, especially physio-somatic and anxiety symptoms. Mucosal activation of the TRYCAT pathway combined with a deficit in natural IgM isotype antibodies to TRYCATs determine cognitive impairments and DAPS/PHEMN symptoms, which together determine to a large extent lowered HR-QoL in schizophrenia.


Assuntos
Qualidade de Vida/psicologia , Esquizofrenia/metabolismo , Psicologia do Esquizofrênico , Aprendizado de Máquina Supervisionado , Triptofano/metabolismo , Adolescente , Adulto , Idoso , Ansiedade/metabolismo , Ansiedade/psicologia , Biomarcadores/metabolismo , Estudos de Casos e Controles , Depressão/metabolismo , Depressão/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Adulto Jovem
14.
J Eval Clin Pract ; 24(4): 879-891, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29790237

RESUMO

RATIONALE: Deficit schizophrenia, as defined by the Schedule for Deficit Syndrome, may represent a distinct diagnostic class defined by neurocognitive impairments coupled with changes in IgA/IgM responses to tryptophan catabolites (TRYCATs). Adequate classifications should be based on supervised and unsupervised learning rather than on consensus criteria. METHODS: This study used machine learning as means to provide a more accurate classification of patients with stable phase schizophrenia. RESULTS: We found that using negative symptoms as discriminatory variables, schizophrenia patients may be divided into two distinct classes modelled by (A) impairments in IgA/IgM responses to noxious and generally more protective tryptophan catabolites, (B) impairments in episodic and semantic memory, paired associative learning and false memory creation, and (C) psychotic, excitation, hostility, mannerism, negative, and affective symptoms. The first cluster shows increased negative, psychotic, excitation, hostility, mannerism, depression and anxiety symptoms, and more neuroimmune and cognitive disorders and is therefore called "major neurocognitive psychosis" (MNP). The second cluster, called "simple neurocognitive psychosis" (SNP) is discriminated from normal controls by the same features although the impairments are less well developed than in MNP. The latter is additionally externally validated by lowered quality of life, body mass (reflecting a leptosome body type), and education (reflecting lower cognitive reserve). CONCLUSIONS: Previous distinctions including "type 1" (positive)/"type 2" (negative) and DSM-IV-TR (eg, paranoid) schizophrenia could not be validated using machine learning techniques. Previous names of the illness, including schizophrenia, are not very adequate because they do not describe the features of the illness, namely, interrelated neuroimmune, cognitive, and clinical features. Stable-phase schizophrenia consists of 2 relevant qualitatively distinct categories or nosological entities with SNP being a less well-developed phenotype, while MNP is the full blown phenotype or core illness. Major neurocognitive psychosis and SNP should be added to the DSM-5 and incorporated into the Research Domain Criteria project.


Assuntos
Reserva Cognitiva/fisiologia , Transtornos Psicóticos , Qualidade de Vida , Esquizofrenia , Triptofano/metabolismo , Aprendizado de Máquina não Supervisionado , Adulto , Sintomas Comportamentais/diagnóstico , Citocinas/imunologia , Feminino , Humanos , Inflamação/imunologia , Masculino , Pessoa de Meia-Idade , Transtornos Neurocognitivos/imunologia , Transtornos Neurocognitivos/psicologia , Neuroimunomodulação , Gravidade do Paciente , Escalas de Graduação Psiquiátrica , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/imunologia , Transtornos Psicóticos/psicologia , Esquizofrenia/diagnóstico , Esquizofrenia/imunologia , Esquizofrenia/fisiopatologia , Psicologia do Esquizofrênico
15.
PLoS One ; 13(5): e0197004, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29763451

RESUMO

BACKGROUND: Both amnestic mild cognitive impairment (aMCI) and schizophrenia, in particular deficit schizophrenia, are accompanied by cognitive impairments. The aim of the present study was to examine the cognitive differences between aMCI and (non)deficit schizophrenia. METHODS: Towards this end we recruited 60 participants with aMCI, 40 with deficit and 40 with nondeficit schizophrenia and 103 normal volunteers. Cognitive measures were assessed with the Consortium to Establish a Registry for Alzheimer's disease (CERAD) using the Verbal Fluency Test (VFT), Boston Naming Test (BNT), Mini-Mental State Examination (MMSE), Word list memory (WLM), Word list recall (WLRecall) and Word list recognition (WLRecognition). Data were analyzed using multivariate analyses and machine learning techniques. RESULTS: BNT scores were significantly lower in aMCI as compared with nondeficit schizophrenia. Patients with deficit schizophrenia had significantly lower MMSE, WLM, WL True Recall and WL Recognition than aMCI patients, while WL False Recall was significantly higher in deficit schizophrenia than in aMCI. Neural network importance charts show that deficit and nondeficit schizophrenia are best separated from aMCI using total BNT score, while WLM and WL false Recall follow at a distance. CONCLUSIONS: Patients with schizophrenia and aMCI have a significantly different neurocognitive profile. Memory impairments, especially in episodic memory, are significantly worse in younger patients with deficit schizophrenia as compared with elderly patients with aMCI, while the latter show more dysnomia than patients with schizophrenia.


Assuntos
Amnésia/fisiopatologia , Disfunção Cognitiva/fisiopatologia , Memória Episódica , Rememoração Mental , Esquizofrenia/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
16.
Dement Geriatr Cogn Disord ; 45(1-2): 38-48, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29617684

RESUMO

BACKGROUND: The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) developed a neuropsychological battery (CERAD-NP) to screen patients with Alzheimer's dementia. Mild cognitive impairment (MCI) has received attention as a pre-dementia stage. OBJECTIVES: To delineate the CERAD-NP features of MCI and their clinical utility to externally validate MCI diagnosis. METHODS: The study included 60 patients with MCI, diagnosed using the Clinical Dementia Rating, and 63 normal controls. Data were analysed employing receiver operating characteristic analysis, Linear Support Vector Machine, Random Forest, Adaptive Boosting, Neural Network models, and t-distributed stochastic neighbour embedding (t-SNE). RESULTS: MCI patients were best discriminated from normal controls using a combination of Wordlist Recall, Wordlist Memory, and Verbal Fluency Test. Machine learning showed that the CERAD features learned from MCI patients and controls were not strongly predictive of the diagnosis (maximal cross-validation 77.2%), whilst t-SNE showed that there is a considerable overlap between MCI and controls. CONCLUSIONS: The most important features of the CERAD-NP differentiating MCI from normal controls indicate impairments in episodic and semantic memory and recall. While these features significantly discriminate MCI patients from normal controls, the tests are not predictive of MCI.


Assuntos
Doença de Alzheimer/diagnóstico , Disfunção Cognitiva/diagnóstico , Aprendizado de Máquina , Testes Neuropsicológicos/normas , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/psicologia , Disfunção Cognitiva/psicologia , Estudos Transversais , Feminino , Humanos , Masculino , Rememoração Mental , Pessoa de Meia-Idade , Redes Neurais de Computação , Reprodutibilidade dos Testes , Fatores Socioeconômicos , Máquina de Vetores de Suporte , Tailândia , Traduções , Comportamento Verbal
17.
Metab Brain Dis ; 33(4): 1053-1067, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29527624

RESUMO

Deficit schizophrenia is characterized by neurocognitive impairments and changes in the patterning of IgA/IgM responses to plasma tryptophan catabolites (TRYCATs). In the current study, supervised pattern recognition methods, including logistic regression analysis (LRA), Support Vector Machine (SVM), and Soft Independent Modeling of Class Analogy (SIMCA), were used to examine whether deficit schizophrenia is a discrete diagnostic class with respect to Consortium To Establish a Registry for Alzheimer's disease (CERAD) and Cambridge Neuropsychological Test Automated Battery (CANTAB) tests and IgA/IgM responses to noxious (NOX) and generally more protective (PRO) TRYCATs. We recruited patients with (n = 40) and without (n = 40) deficit schizophrenia and healthy volunteers (n = 40). The combined use of TRYCAT and CERAD features strongly segregates deficit from nondeficit schizophrenia and healthy controls. Three out of the top five most important features in LRA, SVM and SIMCA agreed, namely two different NOX/PRO TRYCAT ratios and false memory recall. SIMCA shows that deficit schizophrenia is significantly separated from nondeficit schizophrenia and controls with as top 6 features IgA responses to picolinic acid, IgM responses to 3-OH-kynurenine and kynurenic acid, and impairments in Word List Memory and Verbal Fluency Tests and Mini-Mental State Examination. Nevertheless, nondeficit schizophrenia was not significantly separated from controls. The results show that schizophrenia is not a unitary disease with mere continuous differences in severity of illness between apparent subtypes. Deficit schizophrenia is a qualitatively distinct class defined by neuroimmune (autoimmune responses to TRYCATs) and neurocognitive (episodic and semantic memory) features coupled or not with clinical (negative) symptoms.


Assuntos
Citocinas/sangue , Esquizofrenia/diagnóstico , Psicologia do Esquizofrênico , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Esquizofrenia/sangue , Aprendizado de Máquina Supervisionado
18.
Yeast ; 35(1): 99-111, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29027707

RESUMO

To construct a backbone tree consisting of basidiomycetous yeasts, draft genome sequences from 25 species of Trichosporonales (Tremellomycetes, Basidiomycota) were generated. In addition to the hybrid genomes of Trichosporon coremiiforme and Trichosporon ovoides that we described previously, we identified an interspecies hybrid genome in Cutaneotrichosporon mucoides (formerly Trichosporon mucoides). This hybrid genome had a gene retention rate of ~55%, and its closest haploid relative was Cutaneotrichosporon dermatis. After constructing the C. mucoides subgenomes, we generated a phylogenetic tree using genome data from the 27 haploid species and the subgenome data from the three hybrid genome species. It was a high-quality tree with 100% bootstrap support for all of the branches. The genome-based tree provided superior resolution compared with previous multi-gene analyses. Although our backbone tree does not include all Trichosporonales genera (e.g. Cryptotrichosporon), it will be valuable for future analyses of genome data. Interest in interspecies hybrid fungal genomes has recently increased because they may provide a basis for new technologies. The three Trichosporonales hybrid genomes described in this study are different from well-characterized hybrid genomes (e.g. those of Saccharomyces pastorianus and Saccharomyces bayanus) because these hybridization events probably occurred in the distant evolutionary past. Hence, they will be useful for studying genome stability following hybridization and speciation events. Copyright © 2017 John Wiley & Sons, Ltd.


Assuntos
Basidiomycota/genética , Evolução Biológica , Genoma Fúngico , Haploidia , Hibridização Genética , Leveduras/genética
19.
Nat Commun ; 8(1): 1162, 2017 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-29079803

RESUMO

Microbes form fundamental bases of every Earth ecosystem. As their key survival strategies, some microbes adapt to broad ranges of environments, while others specialize to certain habitats. While ecological roles and properties of such "generalists" and "specialists" had been examined in individual ecosystems, general principles that govern their distribution patterns and evolutionary processes have not been characterized. Here, we thoroughly identified microbial generalists and specialists across 61 environments via meta-analysis of community sequencing data sets and reconstructed their evolutionary histories across diverse microbial groups. This revealed that generalist lineages possess 19-fold higher speciation rates and significant persistence advantage over specialists. Yet, we also detected three-fold more frequent generalist-to-specialist transformations than the reverse transformations. These results support a model of microbial evolution in which generalists play key roles in introducing new species and maintaining taxonomic diversity.


Assuntos
Archaea/classificação , Bactérias/classificação , Evolução Biológica , Ecossistema , Animais , Archaea/fisiologia , Fenômenos Fisiológicos Bacterianos , Análise por Conglomerados , Meio Ambiente , Genoma , Humanos , Funções Verossimilhança , Família Multigênica , Filogenia , RNA Ribossômico 16S/genética , Análise de Sequência de DNA
20.
Structure ; 25(1): 132-145, 2017 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-27989623

RESUMO

Anion exchanger 1 (AE1) is a critical transporter and the primary structural scaffold for large macromolecular complexes responsible for erythrocyte membrane flexibility and integrity. We used zero-length crosslinking and mass spectrometry to probe AE1 structures and interactions in intact erythrocyte membranes. An experimentally verified full-length model of AE1 dimers was developed by combining crosslink-defined distance constraints with homology modeling. Previously unresolved cytoplasmic loops in the AE1 C-terminal domain are packed at the domain-domain interface on the cytoplasmic face of the membrane where they anchor the N-terminal domain's location and prevent it from occluding the ion channel. Crosslinks between AE1 dimers and ankyrin-1 indicate the likely topology for AE1 tetramers and suggest that ankyrin-1 wraps around AE1 tetramers, which may stabilize this oligomer state. This interaction and interactions of AE1 with other major erythrocyte membrane proteins show that protein-protein contacts are often substantially more extensive than previously reported.


Assuntos
Proteína 1 de Troca de Ânion do Eritrócito/química , Proteína 1 de Troca de Ânion do Eritrócito/metabolismo , Anquirinas/metabolismo , Membrana Eritrocítica/metabolismo , Proteína 1 de Troca de Ânion do Eritrócito/genética , Reagentes para Ligações Cruzadas , Humanos , Espectrometria de Massas , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Domínios Proteicos , Multimerização Proteica , Homologia Estrutural de Proteína
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