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BACKGROUND AND AIMS: Distinctive gut microbial profiles have been observed between patients with Wilson disease (WD) and healthy individuals. Despite this, the exact relationship and influence of gut microbiota on the advancement of WD-related liver damage remain ambiguous. This research seeks to clarify the gut microbiota characteristics in both human patients and mouse models of WD, as well as their impact on liver injury. METHODS: Gut microbial features in healthy individuals, patients with WD, healthy mice and mice with early- and late-stage WD were analysed using 16S rRNA gene sequencing. Additionally, WD-afflicted mice underwent treatment with either an antibiotic cocktail (with normal saline as a control) or healthy microbiota (using disease microbiota as a control). The study assessed gut microbiota composition, hepatic transcriptome profiles, liver copper concentrations and hepatic pathological injuries. RESULTS: Patients with hepatic WD and mice with WD-related liver injury displayed altered gut microbiota composition, notably with a significant reduction in Lactobacillus abundance. Additionally, the abundances of several gut genera, including Lactobacillus, Veillonella and Eubacterium coprostanoligenes, showed significant correlations with the severity of liver injury in patients with WD. In WD mice, antibiotic treatment or transplantation of healthy microbiota altered the gut microbial structure, increased Lactobacillus abundance and modified the hepatic transcriptional profile. These interventions resulted in reduced hepatic copper concentration and alleviation of WD-related liver injury. CONCLUSIONS: Individuals and mice with pronounced WD-related liver injury exhibited shifts in gut microbial composition. Regulating gut microbiota through healthy microbiota transplantation emerges as a promising therapeutic approach for treating WD-related liver injury.
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INTRODUCTION: Wernekinck commissure syndrome (WCS) is an extremely rare midbrain syndrome, which selectively destroys the decussation of the superior cerebellar peduncle and the central tegmental tract, which commonly presents with bilateral cerebellar ataxia, dysarthria, and internuclear ophthalmoplegia. Palatal myoclonus in Wernekinck commissure syndrome is uncommon and often occurs as a late phenomenon due to hypertrophic degeneration of bilateral inferior olivary nuclei. MATERIAL AND METHOD: A patient with WCS, admitted to our hospital from December 2023, was chosen for this study, and the syndrome's clinical manifestations, imaging features, and etiology were retrospectively analyzed based on the literature. A 68-year-old right-handed East Asian man presented with dizziness, slurred speech, difficulty with swallowing and walking, and rhythmic contractions of the soft palate. He had several risk factors for ischemic cerebrovascular diseases (age, sex, dyslipidemia, hypertension and smoking history). Brain magnetic resonance imaging showed hyperintensity of DWI and hypointensity of ADC at the caudal midbrain which was around the paramedian mesencephalic tegmentum anterior to the aqueduct of midbrain. RESULTS: He was diagnosed with Wernekinck commissure syndrome (WCS) secondary to caudal paramedian midbrain infarction. He was started on dual antiplatelet therapy (aspirin and clopidogrel) and intensive statin therapy. Blood pressure and glucose were also adjusted. His symptoms improved rapidly, and he walked steadily and speak clearly after 7 days of treatment. CONCLUSIONS: Palatal myoclonus is known to occur as a late phenomenon due to hypertrophic degeneration of bilateral inferior olivary nuclei. However, Our case suggests that palatal myoclonus can occur in the early stages in WCS.
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OBJECTIVE: To analyze and explore the risk factors for neurological symptoms in patients with purely hepatic Wilson's disease (WD) at diagnosis. METHODS: This retrospective study was conducted at the First Affiliated Hospital of the Guangdong Pharmaceutical University on 68 patients with purely hepatic WD aged 20.6 ± 7.2 years. The physical examinations, laboratory tests, color Doppler ultrasound of the liver and spleen, and magnetic resonance imaging (MRI) of the brain were performed. RESULTS: The elevated alanine transaminase (ALT) and aspartate transaminase (AST) levels and 24-h urinary copper level were higher in the purely hepatic WD who developed neurological symptoms (NH-WD) group than those in the purely hepatic WD (H-WD) group. Adherence to low-copper diet, and daily oral doses of penicillamine (PCA) and zinc gluconate (ZG) were lower in the NH-WD group than those in the H-WD group. Logistic regression analysis showed that insufficient doses of PCA and ZG were associated with the development of neurological symptoms in patients with purely hepatic WD at diagnosis. CONCLUSION: The development of neurological symptoms in patients with purely hepatic WD was closely associated with insufficient doses of PCA and ZG, and the inferior efficacy of copper-chelating agents. During the course of anti-copper treatment, the patient's medical status and the efficacy of copper excretion should be closely monitored.
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Degeneração Hepatolenticular , Humanos , Encéfalo , Cobre , Degeneração Hepatolenticular/complicações , Degeneração Hepatolenticular/tratamento farmacológico , Penicilamina/uso terapêutico , Estudos Retrospectivos , Fatores de Risco , Zinco/uso terapêuticoRESUMO
Current neural networks are mostly built on the MP model, which usually formulates the neuron as executing an activation function on the real-valued weighted aggregation of signals received from other neurons. This letter proposes the flexible transmitter (FT) model, a novel bio-plausible neuron model with flexible synaptic plasticity. The FT model employs a pair of parameters to model the neurotransmitters between neurons and puts up a neuron-exclusive variable to record the regulated neurotrophin density. Thus, the FT model can be formulated as a two-variable, two-valued function, taking the commonly used MP neuron model as its particular case. This modeling manner makes the FT model biologically more realistic and capable of handling complicated data, even spatiotemporal data. To exhibit its power and potential, we present the flexible transmitter network (FTNet), which is built on the most common fully connected feedforward architecture taking the FT model as the basic building block. FTNet allows gradient calculation and can be implemented by an improved backpropagation algorithm in the complex-valued domain. Experiments on a broad range of tasks show that FTNet has power and potential in processing spatiotemporal data. This study provides an alternative basic building block in neural networks and exhibits the feasibility of developing artificial neural networks with neuronal plasticity.
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BACKGROUND: Aberrant activation of Wnt/ß-catenin signaling by dysregulated post-translational protein modifications, especially ubiquitination is causally linked to cancer development and progression. Although Lys48-linked ubiquitination is known to regulate Wnt/ß-catenin signaling, it remains largely obscure how other types of ubiquitination, such as linear ubiquitination governs its signaling activity. METHODS: The expression and regulatory mechanism of linear ubiquitin chain assembly complex (LUBAC) on Wnt/ß-catenin signaling was examined by immunoprecipitation, western blot and immunohistochemical staining. The ubiquitination status of ß-catenin was detected by ubiquitination assay. The impacts of SHARPIN, a core component of LUBAC on malignant behaviors of gastric cancer cells were determined by various functional assays in vitro and in vivo. RESULTS: Unlike a canonical role in promoting linear ubiquitination, SHARPIN specifically interacts with ß-catenin to maintain its protein stability. Mechanistically, SHARPIN competes with the E3 ubiquitin ligase ß-Trcp1 for ß-catenin binding, thereby decreasing ß-catenin ubiquitination levels to abolish its proteasomal degradation. Importantly, SHARPIN is required for invasiveness and malignant growth of gastric cancer cells in vitro and in vivo, a function that is largely dependent on its binding partner ß-catenin. In line with these findings, elevated expression of SHARPIN in gastric cancer tissues is associated with disease malignancy and correlates with ß-catenin expression levels. CONCLUSIONS: Our findings reveal a novel molecular link connecting linear ubiquitination machinery and Wnt/ß-catenin signaling via SHARPIN-mediated stabilization of ß-catenin. Targeting the linear ubiquitination-independent function of SHARPIN could be exploited to inhibit the hyperactive ß-catenin signaling in a subset of human gastric cancers.
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Carcinogênese/genética , Neoplasias Gástricas/genética , Ubiquitinação/genética , Ubiquitinas/genética , beta Catenina/genética , Humanos , Via de Sinalização Wnt/genéticaRESUMO
BACKGROUND: Bilateral medial medullary infarction (MMI) is uncommon and bilateral medial pons infarction (MPI) is even rarer. "Heart appearance" on magnetic resonance imaging (MRI) is a characteristic presentation of bilateral medial medullary infarction (MMI). CASE PRESENTATION: We present 67-year-old Chinese diabetic and hypertensive female patient affected with "heart appearance-like" infarction in bilateral ponto-medullary junction on MRI. Abnormal signal was observed in the bilateral ponto-medullary junction on T1, T2, fluid-attenuated inversion recovery and apparent diffusion coefficient (ADC). The whole brain digital subtraction angiography (DSA) showed the basilar artery and vertebral artery remained intact. Therefore, we speculated that the bilateral ponto-medullary junction infarction might be caused by the deep perforating branch of the basilar artery. CONCLUSIONS: As far as we know, the "heart appearance-like" infraction in bilateral ponto-medullary junction was not reported. Our case also suggests that bilateral ischemic infraction involvement of the medulla and pon is possible even in the context of an intact basilar artery.
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Infartos do Tronco Encefálico/patologia , Imageamento por Ressonância Magnética , Bulbo/patologia , Idoso , Angiografia Digital , Artéria Basilar/patologia , Encéfalo/patologia , Humanos , Masculino , Ponte/patologia , Artéria Vertebral/patologiaRESUMO
BACKGROUND: Wilson's disease (WD) is an autosomal recessive disease of impaired copper metabolism. Previous study demonstrated that WD with corpus callosum abnormalities (WD-CCA) was limited to the posterior part (splenium). This study aimed to compare clinical features between WD-CCA and WD without corpus callosum abnormalities (WD-no-CCA). METHODS: Forty-one WD patients who had markedly neurological dysfunctions were included in this study. We retrospectively reviewed clinical, biochemical characteristics and MRI findings in the 41 WD patients. All patients were assessed using the Unified Wilson's Disease Rating Scale. RESULTS: Nine patients had corpus callosum abnormalities, 4 of 9 patients had abnormal signal in the genu and splenium, 5 of 9 patients had abnormal signal only in the splenium. WD-CCA had longer course (9.9 ± 4.0 years vs. 3.4 ± 3.6 years, p<0.01), more severe neurological dysfunctions (37.6 vs. 65.9, p<0.01) and higher psychiatric symptoms scores (11.2 vs. 22.5, p<0.01) than WD-no-CCA. The MRI findings indicated that WD-CCA had higher ratio than WD-no-CCA in globus pallidus (88.9% vs. 43.8%, p = 0.024) and thalamus (100% vs. 59.4%, p = 0.038). The index of liver function and copper metabolism had no significant in WD-CCA and WD-no-CCA patients. CONCLUSION: Our findings indicate Wilson's disease can involve the posterior as well as the anterior part of CC and patients with CC involvement had more extensive brain lesions, more severe neurological dysfunctions and psychiatric symptoms.
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Corpo Caloso/patologia , Degeneração Hepatolenticular/patologia , Adulto , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Estudos RetrospectivosRESUMO
BACKGROUND: Persistent primitive trigeminal artery (PPTA) is a rare remnant between the internal carotid artery (ICA) and the basilar artery into adulthood. PPTA generally lacks specific clinical manifestations and occasionally accompanies with other cerebrovascular diseases. CASE PRESENTATION: We reported a 48-year-old Chinese woman who had repeated episodes of transient ischemic attack presented to our hospital. She had no related risk factors of ischemic cerebrovascular diseases. Magnetic resonance image findings demonstrated acute cerebral infraction in centrum semiovale. Magnetic resonance angiography findings indicated right PPTA and ipsilateral hypoplasia of ICA distal anastomosis. CONCLUSIONS: To the best of our knowledge, this is the first report that acute cerebral infarction in a patient with the right PPTA and ipsilateral hypoplasia of ICA distal anastomosis. According to the literature, congenital factor may play an important role in the formation of these vascular anomalies.
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Artéria Basilar/anormalidades , Artéria Carótida Interna/anormalidades , Malformações Vasculares do Sistema Nervoso Central/complicações , Infarto Cerebral/etiologia , Artéria Basilar/diagnóstico por imagem , Artéria Carótida Interna/diagnóstico por imagem , Malformações Vasculares do Sistema Nervoso Central/diagnóstico por imagem , Infarto Cerebral/diagnóstico por imagem , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
Epithelial-mesenchymal transition (EMT) plays a critical role in initiating tumor invasion and metastasis of colorectal cancer (CRC), although the underlying mechanisms remain to be clarified. Herein, we demonstrate that the active form of Rac family small GTPase 1 (RAC1-GTP) is overexpressed in CRCs and promotes the EMT-mediated invasion of CRC cells through activation of the signal transducers and activators of transcription 3 (STAT3) pathway. Increased expression of RAC1-GTP in CRC tissues was positively correlated with the TNM stages of CRCs and indicated poor prognosis of CRC patients. Targeting RAC1-GTP activity by its specific inhibitor NSC23766 markedly suppressed the migration and invasion of CRC cells. Mechanistically, RAC1-GTP directly interacted with STAT3 to promote STAT3 phosphorylation, thus promoted EMT of CRC cells. Enforced expression of constitutively activated STAT3 (STAT3-C) abrogated the suppressive effect of RAC1-GTP disruption on the migration and invasion of CRC cells. Importantly, NSC23766 disrupted EMT in CRC cells and significantly diminished growth of CRC xenografts. Taken together, our data indicate that RAC1-GTP is an important player in EMT-mediated tumor invasion and a potential therapeutic target for CRCs.
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Neoplasias Colorretais/metabolismo , Transição Epitelial-Mesenquimal , Fator de Transcrição STAT3/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Aminoquinolinas/farmacologia , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Neoplasias Colorretais/patologia , Feminino , Células HCT116 , Humanos , Masculino , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Fosforilação , Ligação Proteica , Pirimidinas/farmacologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Proteínas rac1 de Ligação ao GTP/antagonistas & inibidoresRESUMO
MOTIVATION: Cancer is not a single disease and involves different subtypes characterized by different sets of molecules. Patients with different subtypes of cancer often react heterogeneously towards the same treatment. Currently, clinical diagnoses rather than molecular profiles are used to determine the most suitable treatment. A molecular level approach will allow a more precise and informed way for making treatment decisions, leading to a better survival chance and less suffering of patients. Although many computational methods have been proposed to identify cancer subtypes at molecular level, to the best of our knowledge none of them are designed to discover subtypes with heterogeneous treatment responses. RESULTS: In this article we propose the Survival Causal Tree (SCT) method. SCT is designed to discover patient subgroups with heterogeneous treatment effects from censored observational data. Results on TCGA breast invasive carcinoma and glioma datasets have shown that for each subtype identified by SCT, the patients treated with radiotherapy exhibit significantly different relapse free survival pattern when compared to patients without the treatment. With the capability to identify cancer subtypes with heterogeneous treatment responses, SCT is useful in helping to choose the most suitable treatment for individual patients. AVAILABILITY AND IMPLEMENTATION: Data and code are available at https://github.com/WeijiaZhang24/SurvivalCausalTree . CONTACT: weijia.zhang@mymail.uinsa.edu.au. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Biologia Computacional/métodos , Mineração de Dados/métodos , Glioma/tratamento farmacológico , Medicina de Precisão/métodos , Adulto , Neoplasias da Mama/radioterapia , Intervalo Livre de Doença , Feminino , Glioma/radioterapia , Humanos , Resultado do TratamentoRESUMO
BACKGROUND: Tumor-associated macrophages (TAMs) are associated with poor outcomes in multiple solid cancers and play important roles in cancer progression. Epithelial-mesenchymal transition (EMT) may account for metastasis and recurrence. However, the association between TAMs and EMT is not clarified in triple-negative breast cancer (TNBC). The aim of this study was to investigate the effects of TAMs on EMT in TNBC. MATERIAL AND METHODS: We studied specimens from 278 patients with TNBC. TAMs marker cluster of differentiation 163 and EMT-related marker E-cadherin were detected by immunohistochemistry in TNBC tissues, and their clinical significance was evaluated from the patients' medical records. RESULTS: TNBC patients with polarized cluster of differentiation 163+ TAMs infiltration and low level of E-cadherin had a significantly higher risk of aggressive features, including recurrence, histologic differentiation, and lymph node metastasis. Infiltration of TAMs was also negatively correlated with E-cadherin in TNBC tissues. Multivariate analysis indicated that infiltration of TAMs and low expression of E-cadherin were independent prognostic factors of overall survival and disease-free survival in TNBC patients. CONCLUSIONS: High infiltration of TAMs was associated with low expression of E-cadherin and could be used as an unfavorable prognostic factor for patients with TNBC.
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Transição Epitelial-Mesenquimal , Macrófagos/fisiologia , Neoplasias de Mama Triplo Negativas/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Mama/patologia , China/epidemiologia , Feminino , Humanos , Pessoa de Meia-Idade , Receptores de Superfície Celular/metabolismo , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia , Adulto JovemRESUMO
Many optimization tasks must be handled in noisy environments, where the exact evaluation of a solution cannot be obtained, only a noisy one. For optimization of noisy tasks, evolutionary algorithms (EAs), a type of stochastic metaheuristic search algorithm, have been widely and successfully applied. Previous work mainly focuses on the empirical study and design of EAs for optimization under noisy conditions, while the theoretical understandings are largely insufficient. In this study, we first investigate how noisy fitness can affect the running time of EAs. Two kinds of noise-helpful problems are identified, on which the EAs will run faster with the presence of noise, and thus the noise should not be handled. Second, on a representative noise-harmful problem in which the noise has a strong negative effect, we examine two commonly employed mechanisms dealing with noise in EAs: reevaluation and threshold selection. The analysis discloses that using these two strategies simultaneously is effective for the one-bit noise but ineffective for the asymmetric one-bit noise. Smooth threshold selection is then proposed, which can be proved to be an effective strategy to further improve the noise tolerance ability in the problem. We then complement the theoretical analysis by experiments on both synthetic problems as well as two combinatorial problems, the minimum spanning tree and the maximum matching. The experimental results agree with the theoretical findings and also show that the proposed smooth threshold selection can deal with the noise better.
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Algoritmos , Evolução Biológica , Simulação por Computador , Simulação por Computador/normas , Interpretação Estatística de Dados , Modelos TeóricosRESUMO
In real-world optimization tasks, the objective (i.e., fitness) function evaluation is often disturbed by noise due to a wide range of uncertainties. Evolutionary algorithms are often employed in noisy optimization, where reducing the negative effect of noise is a crucial issue. Sampling is a popular strategy for dealing with noise: to estimate the fitness of a solution, it evaluates the fitness multiple ([Formula: see text]) times independently and then uses the sample average to approximate the true fitness. Obviously, sampling can make the fitness estimation closer to the true value, but also increases the estimation cost. Previous studies mainly focused on empirical analysis and design of efficient sampling strategies, while the impact of sampling is unclear from a theoretical viewpoint. In this article, we show that sampling can speed up noisy evolutionary optimization exponentially via rigorous running time analysis. For the (1[Formula: see text]1)-EA solving the OneMax and the LeadingOnes problems under prior (e.g., one-bit) or posterior (e.g., additive Gaussian) noise, we prove that, under a high noise level, the running time can be reduced from exponential to polynomial by sampling. The analysis also shows that a gap of one on the value of [Formula: see text] for sampling can lead to an exponential difference on the expected running time, cautioning for a careful selection of [Formula: see text]. We further prove by using two illustrative examples that sampling can be more effective for noise handling than parent populations and threshold selection, two strategies that have shown to be robust to noise. Finally, we also show that sampling can be ineffective when noise does not bring a negative impact.
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Algoritmos , Evolução Biológica , Modelos Genéticos , HumanosRESUMO
Parkinson's disease (PD) is an insidious onset neurodegenerative disease affecting approximately 1% of the population over the age of 65. So far available therapies for PD have only aimed at improving or alleviating symptoms, but not at slowing, preventing, and reversing the course of PD. Recently, some studies have indicated that the levels and activation of Abelson non-receptor tyrosine kinase (c-Abl, Abl1) were up-regulated in the brain tissue of patients with PD and demonstrated that c-Abl inhibitors could improve motor behavior, prevent the loss of dopamine neurons, inhibit phosphorylation of Cdk5, regulate α-synuclein phosphorylation and clearance, inhibit the tyrosine phosphorylation of parkin and decrease parkin substrate, for example, PARIS (zinc finger protein 746), AIMP2 (aminoacyl-tRNA synthetase-interacting multifunctional protein type2), FBP1 (fuse-binding protein 1), and synphilin-1. Therefore, we review the mechanism of the c-Abl inhibitor in PD and conclude that c-Abl inhibitors may be a potential treatment in PD and other neurodegenerative disease.
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Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/enzimologia , Proteínas Proto-Oncogênicas c-abl/antagonistas & inibidores , Animais , Antiparkinsonianos/farmacologia , Antiparkinsonianos/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Humanos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-abl/metabolismoRESUMO
MOTIVATION: Drosophila melanogaster is a major model organism for investigating the function and interconnection of animal genes in the earliest stages of embryogenesis. Today, images capturing Drosophila gene expression patterns are being produced at a higher throughput than ever before. The analysis of spatial patterns of gene expression is most biologically meaningful when images from a similar time point during development are compared. Thus, the critical first step is to determine the developmental stage of an embryo. This information is also needed to observe and analyze expression changes over developmental time. Currently, developmental stages (time) of embryos in images capturing spatial expression pattern are annotated manually, which is time- and labor-intensive. Embryos are often designated into stage ranges, making the information on developmental time course. This makes downstream analyses inefficient and biological interpretations of similarities and differences in spatial expression patterns challenging, particularly when using automated tools for analyzing expression patterns of large number of images. RESULTS: Here, we present a new computational approach to annotate developmental stage for Drosophila embryos in the gene expression images. In an analysis of 3724 images, the new approach shows high accuracy in predicting the developmental stage correctly (79%). In addition, it provides a stage score that enables one to more finely annotate each embryo so that they are divided into early and late periods of development within standard stage demarcations. Stage scores for all images containing expression patterns of the same gene enable a direct way to view expression changes over developmental time for any gene. We show that the genomewide-expression-maps generated using images from embryos in refined stages illuminate global gene activities and changes much better, and more refined stage annotations improve our ability to better interpret results when expression pattern matches are discovered between genes. AVAILABILITY AND IMPLEMENTATION: The software package is availablefor download at: http://www.public.asu.edu/*jye02/Software/Fly-Project/.
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Biologia Computacional , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Embrião não Mamífero/citologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Processamento de Imagem Assistida por Computador , Algoritmos , Animais , Drosophila melanogaster/embriologia , Embrião não Mamífero/metabolismo , Desenvolvimento Embrionário/genética , Reconhecimento Automatizado de PadrãoRESUMO
To reevaluate the association between the costimulatory molecule cytotoxic T lymphocyte-associated antigen4 (CTLA4) single nucleotide polymorphism (SNP) +49A/G and acute rejection (AR) in renal transplantation, nine studies published before June 2013 were analyzed. Meta-analysis and cumulative meta-analysis (metacum) were performed for each genotype in a random/fixed effect model. The combined odds ratios (OR) with 95% confidence intervals (CI) were calculated to estimate the strength of the association. In the sensitivity analysis, a single study involved in the meta-analysis was deleted each time to investigate the influence of the individual data sets on the pooled ORs. Meta-analysis regression was used for some influence factors, such as year of publication, total number in each group (AR group and control group), ethnicity, the ratio of GG to GA + AA, the ratio of G to A in CTLA4 +49A/G. Overall, a significant correlation was noted between the CTLA4 SNP (+49A/G) and the risk of AR (for GG vs. AG + AA: OR = 1.35, 95% CI = 1.05-1.73, p = 0.02; for G vs. A: OR = 1.21, 95% CI = 1.03-1.42, p = 0.02), especially in the Asian subgroup (for GG vs. AG + AA: OR = 1.79, 95% CI = 1.15-2.78, p = 0.009; for G vs. A: OR = 1.47, 95% CI = 1.04-2.07, p = 0.03). Of the influence factors, the ratio of GG to GA+AA (p = 0.046) and the ratio of G to A (p = 0.017) were significant factors. In conclusion, our results suggest that CTLA4 +49A/G contribute to the risk of AR following renal transplantation.
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Antígeno CTLA-4/genética , Rejeição de Enxerto/genética , Transplante de Rim/efeitos adversos , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Neural network models generally involve two important components, i.e., network architecture and neuron model. Although there are abundant studies about network architectures, only a few neuron models have been developed, such as the MP neuron model developed in 1943 and the spiking neuron model developed in the 1950s. Recently, a new bio-plausible neuron model, flexible transmitter (FT) model (Zhang and Zhou, 2021), has been proposed. It exhibits promising behaviors, particularly on temporal-spatial signals, even when simply embedded into the common feedforward network architecture. This article attempts to understand the properties of the FT network (FTNet) theoretically. Under mild assumptions, we show that: 1) FTNet is a universal approximator; 2) the approximation complexity of FTNet can be exponentially smaller than those of commonly used real-valued neural networks with feedforward/recurrent architectures and is of the same order in the worst case; and 3) any local minimum of FTNet is the global minimum, implying that it is possible to identify global minima by local search algorithms.
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Since acquiring perfect supervision is usually difficult, real-world machine learning tasks often confront inaccurate, incomplete, or inexact supervision, collectively referred to as weak supervision. In this work, we present WSAUC, a unified framework for weakly supervised AUC optimization problems, which covers noisy label learning, positive-unlabeled learning, multi-instance learning, and semi-supervised learning scenarios. Within the WSAUC framework, we first frame the AUC optimization problems in various weakly supervised scenarios as a common formulation of minimizing the AUC risk on contaminated sets, and demonstrate that the empirical risk minimization problems are consistent with the true AUC. Then, we introduce a new type of partial AUC, specifically, the reversed partial AUC (rpAUC), which serves as a robust training objective for AUC maximization in the presence of contaminated labels. WSAUC offers a universal solution for AUC optimization in various weakly supervised scenarios by maximizing the empirical rpAUC. Theoretical and experimental results under multiple settings support the effectiveness of WSAUC on a range of weakly supervised AUC optimization tasks.
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AIM: To investigate the role of PIK3CA oncogene in tumorigenesis and development of esophageal cancer in Chinese patients at the levels of genetic mutation and epigenetics. METHODS: Seventy six esophageal tumor samples and corresponding adjacent normal tissues were collected, and the genomic DNA was extracted. Mutations in the 9th and 20th exons of PIK3CA gene were detected using conventional sequencing. PIK3CA methylation rates in two selected CpG islands (CpG island 1 and 2) were detected using sub-bisulfate modified sequencing. P110α and pAKT expression levels were detected with Western blotting. RESULTS: In PIK3CA gene of the tumor tissues, G1633C (E545Q) mutation was detected in the 9th exon with a rate of 3.95% (3/76), whereas mutation was not found in the 20th exon. Nor mutation did occur in PIK3CA gene of the adjacent normal tissues. The methylation rate of the CpG island 1 had no significant difference between the tumor and adjacent tissues (0.77%±0.009% vs 0.89%±0.008%), but the methylation rate of the CpG island 2 in the esophageal tumors was significantly lower than that in the adjacent tissues (6.00%±2.80% vs 10.45%±5.51%). Furthermore, the rate of methylation of the CpG island 2 in TNM stage III and IV esophageal cancer (3.84%±2.08%) was significantly lower than in stage I (8.52%±2.55%) and stage II (6.42%±2.36%). PIK3CA gene hypomethylation in esophageal cancer was significantly correlated with high expression of p110α. CONCLUSION: PIK3CA gene hypomethylation plays a key role in the tumorigenesis and development of esophageal cancer in Chinese patients, while the mutations of PIK3CA gene have little effect on the development of esophageal cancer.
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Neoplasias Esofágicas/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Adulto , Sequência de Bases , Western Blotting , China , Classe I de Fosfatidilinositol 3-Quinases , Primers do DNA , Ativação Enzimática , Neoplasias Esofágicas/enzimologia , Neoplasias Esofágicas/patologia , Feminino , Humanos , Masculino , Metilação , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: To dynamically investigate the morphology of human gastric cancer SGC-7901 cell clones, and then compare the tumorigenic ability of different clones in order to identify the tumor stem cell clones. METHODS: Clones derived from gastric cancer SGC-7901 cells were assessed by morphological observation, and the clone formation rate and proportion of each clone were calculated. The expression of CD44 and CDX2 in different clones was detected by immunofluorescence microscopy and Western blot. Furthermore, different clones were isolated and cultured, and their self-renewal property was assayed. Cells of different clones were subcutaneously inoculated into nude mice and the tumorigenic ability of each group was determined. RESULTS: Clones derived from gastric cancer SGC-7901 cells had three types, i.e. clones of tight, transitional and loose types. The total clone formation rate was (9.80 ± 1.07)%, and the proportion of tight, transitional and loose type clones was 10.2%, 56.0% and 33.8%, respectively. The results of immunofluorescence microscopic examination showed that the signal of CD44 was significantly stronger in the tight clones than in the transitional and loose clones, however, the signal of CDX2 was weakest in the tight colonies. The results of Western blot were consistent with that of immunofluorescence microscopic observation. SGC-7901 cells of tight clones possessed strong ability of self-renewal and in vivo tumorigenicity in the nude mice. CONCLUSION: SGC-7901 cell clones vary in morphology and differentiation, and the tight type clones may include rich gastric cancer stem cells.