RESUMO
Gene regulatory network plays a crucial role in controlling the biological processes of living creatures. Deciphering the complex gene regulatory networks from experimental data remains a major challenge in system biology. Recent advances in single-cell RNA sequencing technology bring massive high-resolution data, enabling computational inference of cell-specific gene regulatory networks (GRNs). Many relevant algorithms have been developed to achieve this goal in the past years. However, GRN inference is still less ideal due to the extra noises involved in pseudo-time information and large amounts of dropouts in datasets. Here, we present a novel GRN inference method named Normi, which is based on non-redundant mutual information. Normi manipulates these problems by employing a sliding size-fixed window approach on the entire trajectory and conducts average smoothing strategy on the gene expression of the cells in each window to obtain representative cells. To further alleviate the impact of dropouts, we utilize the mixed KSG estimator to quantify the high-order time-delayed mutual information among genes, then filter out the redundant edges by adopting Max-Relevance and Min Redundancy algorithm. Moreover, we determined the optimal time delay for each gene pair by distance correlation. Normi outperforms other state-of-the-art GRN inference methods on both simulated data and single-cell RNA sequencing (scRNA-seq) datasets, demonstrating its superiority in robustness. The performance of Normi in real scRNA-seq data further reveals its ability to identify the key regulators and crucial biological processes.
Assuntos
Algoritmos , Redes Reguladoras de GenesRESUMO
For a given single cell RNA-seq data, it is critical to pinpoint key cellular stages and quantify cells' differentiation potency along a differentiation pathway in a time course manner. Currently, several methods based on the entropy of gene functions or PPI network have been proposed to solve the problem. Nevertheless, these methods still suffer from the inaccurate interactions and noises originating from scRNA-seq profile. In this study, we proposed a cell potency inference method based on cell-specific network entropy, called SPIDE. SPIDE introduces the local weighted cell-specific network for each cell to maintain cell heterogeneity and calculates the entropy by incorporating gene expression with network structure. In this study, we compared three cell entropy estimation models on eight scRNA-Seq datasets. The results show that SPIDE obtains consistent conclusions with real cell differentiation potency on most datasets. Moreover, SPIDE accurately recovers the continuous changes of potency during cell differentiation and significantly correlates with the stemness of tumor cells in Colorectal cancer. To conclude, our study provides a universal and accurate framework for cell entropy estimation, which deepens our understanding of cell differentiation, the development of diseases and other related biological research.
Assuntos
Perfilação da Expressão Gênica , Análise de Célula Única , Entropia , Diferenciação Celular/genética , Análise de Célula Única/métodos , Perfilação da Expressão Gênica/métodos , Análise de Sequência de RNA/métodosRESUMO
PURPOSE: This study aimed to compare non-invasive oscillometric blood pressure (NIBP) measurement with invasive arterial blood pressure (IBP) measurement in patients with sepsis. METHODS: We conducted a retrospective study to evaluate the agreement between IBP and NIBP using the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Paired blood pressure measurements of mean arterial pressure (MAP), systolic blood pressure (SBP), and diastolic blood pressure (DBP) were compared using Bland-Altman analysis and paired Student's t test. We also focus on the effect of norepinephrine (NE) on the agreement between the two methods and the association between blood pressure and mortality during intensive care unit (ICU) stay. RESULTS: A total of 96,673 paired blood pressure measurements from 6060 unique patients were analyzed in the study. In Bland-Altman analysis, the bias (± SD, 95% limits of agreement) was 6.21 mmHg (± 12.05 mmHg, - 17.41 to 29.83 mmHg) for MAP, 0.39 mmHg (± 19.25 mmHg, - 37.34 to 38.12 mmHg) for SBP, and 0.80 mmHg (± 12.92 mmHg, - 24.52 to 26.12 mmHg) for DBP between the two techniques. Similarly, large limits of agreement were shown in different groups of NE doses. NE doses significantly affected the agreement between IBP and NIBP. SBP between the two methods gave an inconsistent assessment of patients' risk of ICU mortality. CONCLUSION: IBP and NIBP were not interchangeable in septic patients. Clinicians should be aware that non-invasive MAP was clinically and significantly underestimated invasive MAP.
Assuntos
Pressão Arterial , Sepse , Humanos , Pressão Sanguínea/fisiologia , Determinação da Pressão Arterial/métodos , Estudos Retrospectivos , Norepinefrina , Sepse/diagnóstico , Monitores de Pressão ArterialRESUMO
Sepsis and its severe form, septic shock, represent the leading cause of death among hospitalized patients. Thioredoxin is a ubiquitous protein essential for cellular redox balance and its aberrant expression is associated with a wide spectrum of inflammation-related pathological conditions. The current study aimed to compare the expression of thioredoxin domain containing 5 (TXNDC5) in septic patients with or without septic shock and to explore the potential regulatory effects of TXNDC5 in sepsis. We analyzed the RNA expression data downloaded from the Gene Expression Omnibus database and measured the plasma level of TXNDC5 in septic patients. The results showed that TXNDC5 was upregulated in patients with septic shock compared to septic patients without shock or healthy controls. We further treated wild-type mice and cultured macrophages with lipopolysaccharide (LPS) and found that TXNDC5 was highly expressed in mice with LPS-induced sepsis and macrophages subjected to LPS stimulation compared to corresponding controls. Then a mouse strain with targeted depletion of Txndc5 was generated. Txndc5 depletion reduced inflammatory cytokine production and affected the recruitment of macrophages and neutrophils into the blood and peritoneum of mice challenged with LPS. Further analysis revealed that TXNDC5 inhibition alleviated LPS-induced sepsis by inhibiting the NF-κB signaling pathway. In summary, these findings suggested that the inhibition of TXNDC5 may be a potential approach to treat sepsis and related syndromes.
Assuntos
Sepse , Choque Séptico , Animais , Humanos , Fatores Imunológicos , Lipopolissacarídeos/toxicidade , Camundongos , NF-kappa B/metabolismo , Isomerases de Dissulfetos de Proteínas , Sepse/metabolismo , Tiorredoxinas/genéticaRESUMO
The pathogenesis of herpes simplex encephalitis (HSE) needs to be fully explored. ß-Arrestin 2 (Arrb2) is highly expressed in brain tissues and plays a key role in the regulation of systemic immune reactions by modulating various signaling pathways. However, the expression of Arrb2 in microglial cells and its influence on HSE prognosis is still undefined. We explore the pathophysiological effect of Arrb2 in the brain using experimental HSE mice. The expression of Arrb2 in microglia was decreased significantly 48 hours following HSV-1 infection. Arrb2 overexpression transgenic (TG) mice had a significantly lower mortality and survival rate was improved by 40% compared to wild-type mice. Arrb2 suppressed the generation of proinflammatory cytokines TNF-α and IL-6 and increased anti-inflammatory cytokines IL-10 and IL-4 expression. Arrb2 also inhibited the activation of the transcription factor NF-κB in microglial cells. Arrb2 TG mice attenuated the blood-brain barrier breakdown and relieved cerebral edema, meanwhile, Arrb2 improved mice neurological function compared with wild-type mice. Overall, Arrb2 favored microglia of the M2 phenotype, attenuated brain proinflammatory responses, protected the blood vessel wall integrity, reduced HSV-1-induced neurological impairment, and improved the survival rate in HSE mice.
Assuntos
Encéfalo/fisiopatologia , Encefalite por Herpes Simples/complicações , Doenças do Sistema Nervoso/prevenção & controle , beta-Arrestina 2/genética , Animais , Encéfalo/virologia , Edema Encefálico/patologia , Edema Encefálico/virologia , Citocinas/imunologia , Modelos Animais de Doenças , Feminino , Herpesvirus Humano 1 , Humanos , Inflamação/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/virologia , NF-kappa B/genética , Doenças do Sistema Nervoso/virologia , Transdução de SinaisRESUMO
Second-generation antipsychotic drug (SGA)-induced metabolic abnormalities, such as dyslipidemia, are a major clinical problem for antipsychotic therapy. Accumulated evidences have shown the efficacy of statins in reducing SGA-induced dyslipidemia, but the underlying mechanisms are unclear. In this study, we explored whether mTOR signaling was involved in olanzapine (OLZ)-induced dyslipidemia as well as the lipid-lowering effects of cotreatment of simvastatin (Sim) in rats. Model rats received OLZ (1.0 mg/kg, t.i.d.) for 7 weeks; from the third week a group of model rats were cotreatment of Sim (3.0 mg/kg, t.i.d.) for 5 weeks. We found that OLZ treatment significantly increased the plasma triglyceride (TG) and total cholesterol (TC) levels, and promoted lipid accumulation in the liver, whereas cotreatment of Sim reversed OLZ-induced dyslipidemia. Hepatic mTORC1 and p-mTORC1 expression was accelerated in the OLZ treatment group, with upregulation of mRNA expression of sterol regulatory element-binding protein 1c (SREBP1c) and its target genes, whereas these alterations were ameliorated by Sim cotreatment. In HepG2 cells, rapamycin (a mTOR inhibitor) significantly reduced the OLZ-stimulated hepatocellular lipid contents and weakened the ability of Sim to lower lipids via a mechanism associated with the upregulation of SREBP1c-mediated de novo lipogenesis. Our data suggest that OLZ induces lipid accumulation in both plasma and liver, and Sim ameliorates OLZ-induced lipid metabolic dysfunction through its effects on mTOR signaling via reducing SREBP1c activation and the downregulation of gene expression involved in lipogenesis. These data provide a new insight into the prevention of metabolic side effects induced by antipsychotic drugs.
Assuntos
Dislipidemias/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Sinvastatina/uso terapêutico , Serina-Treonina Quinases TOR/metabolismo , Animais , Regulação para Baixo , Dislipidemias/induzido quimicamente , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/tratamento farmacológico , Feminino , Células Hep G2 , Humanos , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Fígado/patologia , Olanzapina , Ratos Sprague-Dawley , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismoRESUMO
Congenital muscular dystrophy with laminin-α2 deficiency, also known as MDC1A, displays an extensive phenotypic and genetic heterogeneity. The combination of clinical, biochemical, and genetic findings must be considered to obtain the precise diagnosis and provide appropriate genetic counseling. Here we report one individual from a family presenting with clinical features including seizure attack, slight weakness of proximal leg muscles, and mild cognitive impairment with increased small angular fibers, decreased expression of α-DG and ß-DG, normal expression of laminin-α2, and severe white matter changes. Targeted next-generation sequencing (NGS) revealed two homozygous missense mutations, c.2881G>A (p.Ala961Thr) and c.4406G>A (p.Cys1469Tyr), in LAMA2 in the affected member of the family. Together, these results demonstrate a role for c.2881G>A and c.4406G>A mutations in LAMA2 and show that these two mutations, especially c.4406G>A, may cause mild cognitive impairment, slight motor retardation, seizures, and severe leukoencephalopathy, which extends the clinical spectrum associated with LAMA2 mutations.
Assuntos
Disfunção Cognitiva/genética , Laminina/genética , Leucoencefalopatias/genética , Distrofias Musculares/genética , Adulto , Feminino , Humanos , Distrofias Musculares/fisiopatologia , Mutação de Sentido Incorreto , FenótipoRESUMO
OBJECTIVE: To analyze the clinical phenotypes and features of Guillain-Barré syndrome (GBS) in our hospital and explore the diagnostic value of the Brighton criteria. METHODS: We retrospectively analyzed the clinical data of GBS patients hospitalized in our hospital from January 1, 2013, to September 30, 2016. The patients were affirmatively graded according to the Brighton criteria (highest: level 1, lowest: level 4). RESULT: (1) We enrolled 72 patients with GBS, including 7 with cranial nerve variants, 4 with Miler-Fisher syndrome, and 61 with classic GBS that mainly presented as limb weakness. (2) A total of 56.94% of the included patients had preceding events, of which respiratory tract infections accounted for 63.41%; there was a significant difference in the incidence of GBS across the spring, summer, autumn, and winter. Weakness was the first symptom in 75% of patients, all patients reached peaked within 4 weeks, and 94.44% of the patients presented with decreased or absent deep tendon reflexes. Among the patients who completed a lumbar puncture cerebrospinal fluid (CSF) examination, 73.24% showed proteins dissociated from CSF cells. Demyelinating GBS was found in 54%, and axonal GBS was found in 22% of the patients who completed an electrophysiological examination. All patients with classic GBS were graded according to the Brighton diagnostic criteria as level 1 (60.66%, 37/61), level 2 (34.42%, 21/61), level 3 (4.92%, 3/61), or level 4 (0%). CONCLUSION: In our hospital, the clinical features of patients with GBS were similar to those described in previous studies, but demyelinating GBS was the most important subtype. Most preceding events were upper respiratory tract infections. The Brighton criteria were highly sensitive, and perfect clinical data improved diagnostic grading. In areas where medical resources are relatively scarce, a detailed medical history and physical examination can help improve diagnostic accuracy.
Assuntos
Síndrome de Guillain-Barré/diagnóstico , Adulto , Idoso , Feminino , Síndrome de Guillain-Barré/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/etiologia , Fenótipo , Estudos RetrospectivosRESUMO
BACKGROUND: The surgical approaches to thoracolumbar junction (T12-L1) tuberculosis were controversial. We aimed to compare the safety and efficacy of three different procedures through a multicentre retrospective study. METHODS: The medical records of thoracolumbar junction tuberculosis patients (n = 177) from January 2005 to January 2015 were collected and reviewed. Forty-five patients underwent anterior debridement and instrumented fusion (Group A), 52 underwent anterior combined with posterior debridement and instrumented fusion (Group B) and 80 underwent posterior-only debridement and instrumented fusion (Group C). Patients with neurological deficit were 10 in Group A, 23 in Group B, 36 in Group C. All patients had a standard preoperative and postoperative anti - tuberculous therapy regimen. Clinical outcomes, laboratory indexes and radiological evaluation of the three groups were compared. Operations at each centre were performed by the respective senior medical teams of the six different hospitals. RESULTS: All three surgical approaches achieved bone fusion and pain relief. Cases with neurological deficits had different degrees of improvement after surgery. The operative time was 330.2 ± 45.4 min, 408.0 ± 54.3 min, 227.9 ± 58.5 min, and the blood loss was 744.0 ± 193.8 ml, 1134.6 ± 328.2 ml, 349.8 ± 289.4 ml in groups A, B and C respectively. The average loss of correction was 5.5 ± 3.7° in group A, 1.6 ± 1.9° in group B, 1.7 ± 2.2° in group C, and the difference between groups except B vs C were of statistically significant (P < 0.05). CONCLUSIONS: For patients with thoracolumbar junction (T12-L1) tuberculosis, the posterior-only procedure is the better than the anterior-only procedure in the correction of kyphosis and maintenance of spinal stability. The posterior-only procedure is recommended because it achieves the same efficacy as combined procedure with shorter operation time, less blood loss and trauma.
Assuntos
Dor nas Costas/terapia , Desbridamento/efeitos adversos , Vértebras Lombares/cirurgia , Fusão Vertebral/efeitos adversos , Vértebras Torácicas/cirurgia , Tuberculose da Coluna Vertebral/terapia , Adolescente , Adulto , Antituberculosos/uso terapêutico , Dor nas Costas/diagnóstico , Dor nas Costas/etiologia , Perda Sanguínea Cirúrgica/estatística & dados numéricos , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Fixadores Internos/efeitos adversos , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/patologia , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Medição da Dor , Estudos Retrospectivos , Fusão Vertebral/instrumentação , Fusão Vertebral/métodos , Vértebras Torácicas/diagnóstico por imagem , Vértebras Torácicas/patologia , Resultado do Tratamento , Tuberculose da Coluna Vertebral/complicações , Tuberculose da Coluna Vertebral/diagnóstico por imagem , Tuberculose da Coluna Vertebral/patologia , Adulto JovemRESUMO
BACKGROUND: A multicentre retrospective study was conducted to evaluate the safety and efficacy of single-stage posterior debridement, decompression and transpedicular screw fixation for the treatment of thoracolumbar junction (T12-L1) tuberculosis in patients with associated neurological deficit. METHODS: Thoracolumbar junction (T12-L1) tuberculosis patients (n = 69) with neurological deficit who underwent single-stage posterior debridement, decompression and transpedicular screw fixation from January 2005 to January 2015 were included in the study. Antituberculosis therapy was performed both before and after surgery. The surgery duration and patient blood loss were evaluated, in addition to the change in pain visual analogue score (pVAS), kyphotic angle, Oswestry disability index (ODI) score and American Spinal Injury Association (ASIA) grade assessed preoperatively, immediate postoperatively and at the final follow-up visit. RESULTS: The average blood loss was 354 ± 291 mL. The average kyphosis angle was corrected from 21 ± 9° preoperatively to 9 ± 4° postoperatively, with a mean decrease in pVAS and ODI scores of 3.4 and 16, respectively. The postoperative ASIA grading was grade A for five patients, grade C for 15 and grade D for 49 patients, which had improved to grade C for four patients, grade D for three patients and grade E for 62 patients at the final follow-up. The neurological deficit did not worsen in any of the patients. CONCLUSIONS: Single-stage posterior debridement, decompression and transpedicular screw fixation is an effective treatment method in thoracolumbar junction (T12-L1) tuberculosis patients with neurological deficit, with good neurological recovery and no progression of kyphosis.
Assuntos
Desbridamento/métodos , Descompressão Cirúrgica/métodos , Vértebras Lombares/cirurgia , Doenças do Sistema Nervoso/cirurgia , Vértebras Torácicas/cirurgia , Tuberculose da Coluna Vertebral/cirurgia , Adolescente , Adulto , Parafusos Ósseos , Desbridamento/instrumentação , Descompressão Cirúrgica/instrumentação , Feminino , Seguimentos , Humanos , Vértebras Lombares/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/diagnóstico por imagem , Doenças do Sistema Nervoso/epidemiologia , Estudos Retrospectivos , Vértebras Torácicas/diagnóstico por imagem , Tuberculose da Coluna Vertebral/diagnóstico por imagem , Tuberculose da Coluna Vertebral/epidemiologia , Adulto JovemRESUMO
Eosinophilic fasciitis is a rare scleroderma-like syndrome with an unknown aetiology. The characteristics of this disorder include lymphoplasmacytic inflammation involving the subcutaneous fat septa and fascia. Eosinophilic myositis is diagnosed when inflammation extends into the muscles. Here, we describe four patients who developed eosinophilic fasciitis, three of whom developed eosinophilic fasciitis with myositis. Fascial and muscle biopsies were used to confirm the diagnoses. All the patients presented with musculoskeletal symptoms; their electromyographic examinations showed myogenic lesions [short-duration, low-amplitude and polyphasic motor unit action potentials (MUPs), so-called myopathic changes, frequently with abnormal spontaneous activity], in contrast with findings from other reports.
Assuntos
Eosinofilia/patologia , Fasciite/patologia , Miosite/patologia , Adolescente , Adulto , Biópsia , Eletromiografia , Feminino , Humanos , Masculino , Mialgia/etiologia , Adulto JovemRESUMO
Purpose: To identify the regularity of signal evolution of intracerebral hemorrhage on susceptibility-weighted imaging (SWI) at different stages compared with T1-weighted imaging (T1WI) and T2-weighted imaging (T2WI). Methods: We retrospectively evaluated a series of 365 patients who underwent T1WI, T2WI, and SWI examination simultaneously or sequentially in our hospital from January 2015 to May 2017. Two neuroradiologists assessed the images and discrepancies between their interpretations were resolved by consensus. Statistical analysis was performed using Chi-squared and Kappa tests. Results: Of the 365 patients on SWI sequence, 94 were enrolled. SWI detected the cases at different stages; T1WI detected 89 cases and T2WI detected 91 cases. The signal intensity of intracerebral hemorrhage on SWI was significantly associated with T1WI imaging and T2WI (χ2 = 4.651; p < 0.05; χ2 = 26.396; p < 0.01, respectively), especially at the late subacute stage. There was moderate consistency between the signal intensity of intracerebral hemorrhage on T2WI and SWI (Kappa coefficient = 0.530). Conclusion: Intracerebral hemorrhage has a varied appearance on SWI, and the evolution of signal of intracerebral hemorrhage on SWI sequence is influenced by T1WI and T2WI. Hematoma detection should be closely combined with clinical manifestation.
Assuntos
Hemorragia Cerebral/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Hemorragia Cerebral/epidemiologia , Feminino , Humanos , Masculino , Estudos RetrospectivosRESUMO
Background: Osteoporosis is a disease associated with bone resorption, characterized primarily by the excessive activation of osteoclasts. Ginkgetin is a compound purified from natural ginkgo leaves which has various biological properties, including anti-inflammation, antioxidant, and anti-tumor effects. This study investigated the bone-protective effects of ginkgetin in ovariectomized (OVX) mice and explored their potential signaling pathway in inhibiting osteoclastogenesis in a mouse model of osteoporosis. Methods: Biochemical assays were performed to assess the levels of Ca, ALP, and P in the blood. Micro CT scanning was used to evaluate the impact of ginkgetin on bone loss in mice. RT-PCR was employed to detect the expression of osteoclast-related genes (ctsk, c-fos, trap) in their femoral tissue. Hematoxylin and eosin (H&E) staining was utilized to assess the histopathological changes in femoral tissue due to ginkgetin. The TRAP staining was used to evaluate the impact of ginkgetin osteoclast generation in vivo. Western blot analysis was conducted to investigate the effect of ginkgetin on the expression of p-NF-κB p65 and IκBα proteins in mice. Results: Our findings indicate that ginkgetin may increase the serum levels of ALP and P, while decreasing the serum level of Ca in OVX mice. H&E staining and micro CT scanning results suggest that ginkgetin can inhibit bone loss in OVX mice. The TRAP staining results showed ginkgetin suppresses the generation of osteoclasts in OVX mice. RT-PCR results demonstrate that ginkgetin downregulate the expression of osteoclast-related genes (ctsk, c-fos, trap) in the femoral tissue of mice, and this effect is dose-dependent. Western blot analysis results reveal that ginkgetin can inhibit the expression of p-NF-κB p65 and IκBα proteins in mice. Conclusion: Ginkgetin can impact osteoclast formation and activation in OVX mice by inhibiting the NF-κB/IκBα signaling pathway, thereby attenuating bone loss in mice.
Assuntos
Biflavonoides , NF-kappa B , Osteoclastos , Transdução de Sinais , Animais , Biflavonoides/farmacologia , Biflavonoides/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Camundongos , NF-kappa B/metabolismo , Feminino , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteoporose/tratamento farmacológico , Osteoporose/metabolismo , Osteoporose/patologia , Ovariectomia , Modelos Animais de Doenças , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/metabolismo , Reabsorção Óssea/prevenção & controle , Reabsorção Óssea/patologia , Microtomografia por Raio-X , Inibidor de NF-kappaB alfa/metabolismo , Camundongos Endogâmicos C57BLRESUMO
Background: Diabetic ketoacidosis (DKA) is a frequent acute complication of diabetes mellitus (DM). It develops quickly, produces severe symptoms, and greatly affects the lives and health of individuals with DM.This article utilizes machine learning methods to examine the baseline characteristics that significantly contribute to the development of DKA. Its goal is to identify and prevent DKA in a targeted and early manner. Methods: This study selected 2382 eligible diabetic patients from the MIMIC-IV dataset, including 1193 DM patients with ketoacidosis and 1186 DM patients without ketoacidosis. A total of 42 baseline characteristics were included in this research. The research process was as follows: Firstly, important features were selected through Pearson correlation analysis and random forest to identify the relevant physiological indicators associated with DKA. Next, logistic regression was used to individually predict DKA based on the 42 baseline characteristics, analyzing the impact of different physiological indicators on the experimental results. Finally, the prediction of ketoacidosis was performed by combining feature selection with machine learning models include logistic regression, XGBoost, decision tree, random forest, support vector machine, and k-nearest neighbors classifier. Results: Based on the importance analysis conducted using different feature selection methods, the top five features in terms of importance were identified as mean hematocrit (haematocrit_mean), mean hemoglobin (haemoglobin_mean), mean anion gap (aniongap_mean), age, and Charlson comorbidity index (charlson_comorbidity_index). These features were found to have significant relevance in predicting DKA. In the individual prediction using logistic regression, these five features have been proven to be effective, with F1 scores of 1.000 for hematocrit mean, 0.978 for haemoglobin_mean, 0.747 for age, 0.692 for aniongap_mean and 0.666 for charlson_comorbidity_index. These F1 scores indicate the effectiveness of each feature in predicting DKA, with the highest score achieved by mean hematocrit. In the prediction of DKA using machine learning models, including logistic regression, XGBoost, decision tree, and random forest demonstrated excellent results, achieving an F1 score of 1.000. Additionally, by applying feature selection techniques, noticeable improvements were observed in the experimental performance of the support vector machine and k-nearest neighbors classifier. Conclusion: The study found that hematocrit, hemoglobin, anion gap, age, and Charlson comorbidity index are closely associated with ketoacidosis. In clinical practice, these five baseline characteristics should be given with the special attention to achieve early detection and treatment, thus reducing the incidence of the disease.
Assuntos
Diabetes Mellitus , Cetoacidose Diabética , Humanos , Lactente , Cetoacidose Diabética/diagnóstico , Cetoacidose Diabética/epidemiologia , Cetoacidose Diabética/etiologia , HemoglobinasRESUMO
OBJECTIVE: Prior researchers have identified distinct differences in functional connectivity neuroimaging characteristics among MDD patients. However, the auxiliary diagnosis and subtype differentiation roles of VMHC values in MDD patients have yet to be fully understood. We aim to explore the separating ability of VMHC values in patients with anxious MDD or with non-anxious MDD and HCs. METHODS: We recruited 90 patients with anxious MDD, 69 patients with non-anxious MDD and 84 HCs. We collected a set of clinical variables included HAMD-17 scores, HAMA scores and rs-fMRI data. The data were analyzed combining difference analysis, SVM, correlation analysis and ROC analysis. RESULTS: Relative to HCs, non-anxious MDD patients displayed significant lower VMHC values in the insula and PCG, and anxious MDD patients displayed a significant decrease in VMHC values in the cerebellum_crus2, STG, postCG, MFG and IFG. Compared with non-anxious MDD patients, the anxious MDD showed significant enhanced VMHC values in the PCG. The VMHC values in the insula and cerebellum_crus2 regions showed a better ability to discriminate HCs from patients with non-anxious MDD or with anxious MDD. The VMHC values in PCG showed a better ability to discriminate patients with anxious MDD and non-anxious MDD patients. CONCLUSION: The VMHC values in the insula and cerebellum_crus2 regions could be served as imaging markers to differentiate HCs from patients with non-anxious MDD or with anxious MDD respectively. And the VMHC values in the PCG could be used to discriminate patients with anxious MDD from the non-anxious MDD patients.
RESUMO
Thioredoxin1 (TRX1) is a key protein that regulates redox and is considered to be a key target for cancer therapy. Flavonoids have been proven to have good antioxidant and anticancer activities. This study aimed to investigate whether the flavonoid calycosin-7-glucoside (CG) exerts an anti-hepatocellular carcinoma (HCC) role by targeting TRX1. Different doses of CG were used to treat HCC cell lines Huh-7 and HepG2 to calculate the IC50. On this basis, the effects of low, medium and high doses of CG on cell viability, apoptosis, oxidative stress and TRX1 expression of HCC cells were investigated in vitro. Also, HepG2 xenograft mice were used to evaluate the role of CG on HCC growth in vivo. The binding mode of CG and TRX1 was explored by molecular docking. Then si-TRX1 was used to further discover the effects of TRX1 on CG inhibition of HCC. Results found that CG dose-dependent decreased the proliferation activity of Huh-7 and HepG2 cells, induced apoptosis, significantly activated oxidative stress and inhibited TRX1 expression. In vivo experiments also showed that CG dose-dependent regulated oxidative stress and TRX1 expression, and promoted the expression of apoptotic proteins to inhibit HCC growth. Molecular docking confirmed that CG had a good binding effect with TRX1. Intervention with TRX1 significantly inhibited the proliferation of HCC cells, promoted apoptosis, and further promoted the effect of CG on the activity of HCC cells. In addition, CG significantly increased ROS production, reduced mitochondrial membrane potential, regulated the expression of Bax, Bcl-2 and cleaved-caspase-3, and activated mitochondria-mediated apoptosis. And si-TRX1 enhanced the effects of CG on mitochondrial function and apoptosis of HCC, suggesting that TRX1 participated in the inhibitory effect of CG on mitochondria-mediated apoptosis of HCC. In conclusion, CG exerts anti-HCC activity by targeting TRX1 to regulate oxidative stress and promote mitochondria-mediated apoptosis.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Camundongos , Animais , Neoplasias Hepáticas/patologia , Tiorredoxinas/metabolismo , Simulação de Acoplamento Molecular , Linhagem Celular Tumoral , Carcinoma Hepatocelular/patologia , Apoptose , Mitocôndrias , Células Hep G2 , Estresse Oxidativo , Proliferação de CélulasRESUMO
Autophagy is an efficient and attractive protein degradation pathway in addition to the ubiquitin-proteasome system. Herein, systematic optimization of coumarin analogs linked with the CDK9 inhibitor SNS-032 is reported that may bind to cyclin-dependent kinase 9 (CDK9) and microtubule-associated protein 1 light chain 3 beta (LC3B) simultaneously, which leads to the selective autophagic degradation of targeted CDK9/cyclin T1 and is different from the PROTAC degrader THAL-SNS-032. Further mechanism studies revealed an autophagy-lysosome pathway, where the degraders possibly formed a ternary complex with CDK9 and LC3B. In addition, degrader 10 showed antitumor efficacy in vivo. Our work optimized a potent LC3B recruiter and demonstrated the feasibility of autophagy-tethering compounds (ATTECs), which could be applied for the degradation of diverse intracellular pathogenic proteins to treat related diseases.
Assuntos
Quinase 9 Dependente de Ciclina , Proteínas Associadas aos Microtúbulos , Ciclina T , Proteínas Associadas aos Microtúbulos/metabolismo , Cumarínicos/farmacologiaRESUMO
The cellular prion protein (PrPC) is required for skeletal muscle function. Here, we report that a higher level of PrPC accumulates in the cytoplasm of the skeletal muscle of six myopathy patients compared to controls. PrPC inhibits skeletal muscle cell autophagy, and blocks myoblast differentiation. PrPC selectively binds to a subset of miRNAs during myoblast differentiation, and the colocalization of PrPC and miR-214-3p was observed in the skeletal muscle of six myopathy patients with excessive PrPC. We demonstrate that PrPC is overexpressed in skeletal muscle cells under pathological conditions, inhibits muscle cell differentiation by physically interacting with a subset of miRNAs, and selectively recruits these miRNAs into its phase-separated condensate in living myoblasts, which in turn enhances liquid-liquid phase separation of PrPC, promotes pathological aggregation of PrP, and results in the inhibition of autophagy-related protein 5-dependent autophagy and muscle bundle formation in myopathy patients characterized by incomplete muscle regeneration.
Assuntos
MicroRNAs , Doenças Musculares , Proteínas PrPC , Humanos , Diferenciação Celular/genética , Proliferação de Células , MicroRNAs/genética , MicroRNAs/metabolismo , Desenvolvimento Muscular/fisiologia , Músculo Esquelético/metabolismo , Doenças Musculares/metabolismo , Proteínas PrPC/metabolismoRESUMO
Phthalides, an important class of bioactive natural products, are widely distributed in plants, fungi, lichens, and liverworts. Amon them, n-butylphthalide, a phthalide monomer, has been approved to cure ischemic stroke. Owing to their good bioactivities in anti-microbial, anti-inflammatory, anti-tumor, anti-diabetic, and other aspects, a large number of researches have been conducted on phthalides from nature materials. In recent years, hundreds of novel natural phthalides were obtained. This review provides profiles of the advances in the distribution, chemistry, and biological activities of natural phthalides in 2016-2022.
Assuntos
Fungos , Plantas , Anti-Inflamatórios/farmacologia , Benzofuranos , Estrutura MolecularRESUMO
Background: Olanzapine (OLZ) is an antipsychotic with a high risk of metabolic syndrome, and its induced metabolic disturbance may be related to the thermogenic function of brown adipose tissue (BAT). Of note is that schizophrenia itself appears to be associated with a higher incidence of metabolic syndrome. However, whether OLZ affects metabolic disorders by regulating BAT function and its mechanism in animal models of schizophrenia have not been reported. Methods: We induced maternal immune activation (MIA) in pregnant rodents by injection of synthetic double-stranded RNA-poly I:C (a virus-like substance), and rats were injected with poly I:C, 10 mg/kg) or saline on day 13 of gestation. Rat offspring received OLZ (1 mg/kg, tid) or vehicle from adulthood for 28 days, and body weight and food intake were recorded. Morphological alterations of white adipose tissue (WAT) and BAT were analyzed by HE and oil red staining, and expression of BAT-specific marker proteins/genes was detected by western blot and qRT-PCR. In addition, embryonic stem cells C3H10T1/2 were used to direct differentiation into brown-like adipocytes, and C3H10T1/2 cells were treated with OLZ for the differentiation process. The effects of OLZ on brown-like adipocyte differentiation and activity were analyzed using oil red staining, immunofluorescence and flow cytometry. Results: Compared with the Veh (saline) group, the TG, pWAT weight, adipocyte size and liver weight of the Veh (poly I:C) group were significantly increased, suggesting that the offspring of Poly I:C rats had obvious dyslipidemia and lipid accumulation, which were risk factors for metabolic abnormalities such as obesity. In addition, OLZ treatment resulted in altered WAT and BAT morphology in poly I:C or saline exposed offspring, causing lipid accumulation and weight gain and reducing the expression of the BAT-specific marker molecule UCP1 protein/gene. At the same time, OLZ inhibited the directional differentiation and mitochondrial activity of C3H10T1/2 brown-like adipocytes. Conclusion: Poly I:C-elicited MIA and OLZ differentially inhibited BAT activity and mitochondrial biogenesis, leading to weight gain in adult rats, a process involving PPAR-γ/UCP1-related thermogenic proteins.